Optically active 1-phenyl-2-substituted propane derivatives and methods of producing the same

ABSTRACT

An (S)-1-phenyl-2-substituted propane derivative shown by the following formula (I)                    
     wherein R 1  and R 2  represent a lower alkyl group, etc., or R 1  and R 2  may form together an alkylene group, etc.; R 3 , R 4  and R 5  represent a hydrogen atom, etc.; and X represents a hydroxyl group which may be protected with a protective group, or a halogen atom etc., can readily be produced (i) by permitting a microorganism belonging to the genus Torulaspora, the genus Candida, the genus Pichia or the like to act on a phenylacetone derivative and asymmetrically reducing the compound, or (ii) by sterically inverting an (R)-enantiomer. (R,R)-1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol derivative having a high optical purity can easily be obtained from the compound of the formula (I). The ethanol derivative is useful as an anti-obesity agent and the like.

This is a division of application Ser. No. 08/883,664, filed Jun. 27,1997, now U.S. Pat. No. 5,902,900 which was a division of applicationSer. No. 08/613,946 filed Mar. 13, 1996, now U.S. Pat. No. 5,679,557.

FIELD OF THE INVENTION

The present invention relates to an optically active (S)- or(P)-1-phenyl-2-substituted propane derivative which is an importantintermediate for synthesis of an(R,R)-1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol derivative, anda method of producing the same. The present invention further relates toa method of producing the ethanol derivative which is useful as amedical compound or an intermediate product thereof.

BACKGROUND OF THE INVENTION

As anti-obesity agents or anti-diabetic agents belonging to a newcategory of agents without using insulin,1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol derivatives are notedsince the derivatives act selectively on a β₃-receptor in vivo, thushaving extremely low side effects. Pharmacological studies on the1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol derivatives haverevealed that the β₃-action substantially depends on (R,R)-enantiomersthereof (see J. Med. Chem., 35, 3081 (1992), and U.S. Pat. No.5,061,727). For example, the above-mentioned U.S. Patent discloses thatan(R,R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylicacid disodium salt has a higher activity than the corresponding(S,S)-enantiomer by a factor of 47.

For the production of an optically active1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol derivative, there isknown an optical resolution of a racemic form or a racemate, or anasymmetric synthesis.

For example, the above mentioned U.S. Pat. No. 5,061,727 discloses amethod of producing an(R,R)-1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol derivative whichcomprises (1) allowing a racemic 2-amino-1-phenylethanol derivative toreact with a phenylacetone derivative and sodium cyanoborohydride toproduce a mixture of four species of optical isomers of a1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol derivative, (2)isolating and removing an (R,S)-isomer and an (S,R)-isomer from themixture, and (3) optically resoluting an (R,R)-isomer and an(S,S)-isomer by a diastereomer method. According to this method,however, it is necessary to isolate and purify only the (R,R)-isomerfrom the mixture of the four species of optical isomers, therefore, theprocesses are complicated and the yield is decreased. Further, sincelarge quantities of raw materials are required, the method is alsodisadvantageous in economical factor.

The U.S. Patent and the Journal of Medicinal Chemistry as mentionedabove disclose a method allowing an (R)-3-chlorostyrene oxide derivativeto react with an (R)-1-methyl-2-phenylethylamine derivative. The(R)-1-methyl-2-phenylethylamine derivative used as a raw material orreactant in the method, however, has a strong antihypnotic or arousalaction and it requires a particular attention when handled, therefore isnot suited for a use in commercial production. Further, a lot of stepsor processes are required to obtain the above-mentioned two reactants.For instance, the (R)-3-chlorostyrene oxide derivative is prepared froman acetophenone derivative through three steps, that is, chlorination,asymmetric reduction and epoxidation, and the(R)-1-methyl-2-phenylethylamine derivative is prepared from L-DOPAthrough six steps, namely, introduction of a protective group into anamino group, esterification, reduction of the resulting ester,converting a hydroxyl group to a mesyloxy group, removal of theprotective group and reduction.

SUMMARY OF THE INVENTION

Accordingly, it is an object of the present invention to provide anoptically active compound which is useful for the efficient productionof an (R,R)-1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol derivativewith a good yield.

It is another object of the invention to provide a process for producingthe compound efficiently with high yield and optical purity.

Still another object of the invention is to provide an optically activecompound which is useful for the production of the derivative and isavailable and easy to handle or treat.

It is a further object of the present invention to provide a process forproducing an (R,R)-1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanolderivative having a higher optical purity efficiently with a high yield.

A yet further object of the present invention is to provide an opticallyactive (R)-enantiomer which is suitable for the production of theoptically active compound being useful for producing the(R,R)-1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol derivative, anda process for producing the same.

The present invention further relates to a process for asymmetricallyreducing an phenylacetone derivative to the optically active compound,and to a use of a microorganism in production of the optically activeintermediate.

After much studies and efforts to accomplish the above mentionedobjects, the present inventors found that an optically active (S)- or(R)-1-phenyl-2-substituted propane derivative having a high opticalpurity can be obtained with a high yield by permitting a microorganismcapable of asymmetrically reducing a phenylacetone derivative to act onthe phenylacetone derivative, and that an optically active(R,R)-1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol derivative caneasily or readily be produced from the (S)- or(R)-1-phenyl-2-substituted propane derivative with high yield andselectivity. The present invention has been accomplished based on theabove findings.

Thus, the present invention provides an (S)-1-phenyl-2-substitutedpropane derivative shown by the following formula (I)

wherein R¹ and R² represent (a) the same or different, a hydrogen atomor a protective group for hydroxyl group, or (b) R¹ and R² may form anoptionally substituted ring with the adjacent oxygen atoms; R³, R⁴ andR⁵ independently represent a hydrogen atom, a lower alkyl group, a lowerhaloalkyl group, a lower alkoxy group, a nitro group or a halogen atom;and X represent a hydroxyl group which may be protected with aprotective group, an optionally substituted alkylsulfonyloxy group, anoptionally substituted arylsulfonyloxy group or a halogen atom.

The (S)-1-phenyl-2-substituted propane derivative of the general formula(I) may be produced by, for example, a process which comprises:

permitting a microorganism which is capable of asymmetrically reducing aphenylacetone derivative shown by the following formula (II)

wherein R¹, R², R³, R⁴ and R⁵ have the same meanings as defined above,to a corresponding (S)-1-phenyl-2-propanol derivative shown by thefollowing formula (III)

wherein R¹, R², R³, R⁴ and R⁵ have the same meanings as defined above,or a preparation thereof

to act on the phenylacetone derivative, and harvesting or recovering theproduct (S)-1-phenyl-2-propanol derivative.

Further, the (S)-1-phenyl-2-substituted propane derivative of thegeneral formula (I) may also be obtained by, for instance, allowing asulfonylating agent or a halogenating agent to react with the(S)-1-phenyl-2-propanol derivative of the general formula (III).

The (S)-1-phenyl-2-substituted propane derivative of the general formula(I) is useful for production of an(R,R)-1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol derivative shownby the following formula (VI)

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and Z have the samemeanings as defined above, or a salt thereof.

The present invention further provides an (R)-1-phenyl-2-substitutedpropane derivative shown by the general formula (VII)

wherein R¹, R², R³, R⁴, R⁵ and X have the same meanings as definedabove.

The (R)-1-phenyl-2-substituted propane derivative of the general formula(VII) may be produced by, for instance, utilizing a function of amicroorganism which is capable of asymmetrically reducing thephenylacetone derivative of the general formula (II) to produce thecorresponding (R)-1-phenyl-2-propanol derivative shown by the followingformula (VII′)

wherein R¹, R², R³, R⁴ and R⁵ have the same meanings as defined above,or a preparation thereof.

The (R)-1-phenyl-2-substituted propane derivative of the general formula(VII) may, for instance, be sterically inverted to the(S)-1-phenyl-2-substituted propane derivative of the general formula (I)with the use of a nucleophilic reagent.

The present invention still further discloses a process forasymmetrically reducing the phenylacetone derivative of the generalformula (II) to the corresponding (S)- or (R)-1-phenyl propanederivative, and a use of a microorganism capable of asymmetricallyreducing the phenylacetone derivative of the general formula (II), or apreparation thereof for the production of the corresponding (S)- or(R)-1-phenyl-2-substituted propane derivative.

DETAILED DESCRIPTION OF THE INVENTION

The (S)-1-phenyl-2-substituted propane derivatives shown by the generalformula (I) are particularly useful as intermediates for synthesis ofthe (R,R)-1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol derivativeswhich are usable as medicinal compounds or drugs, or intermediatematerials thereof.

As the protective group for hydroxyl group in R¹ and R², there may bementioned protective groups for a hydroxyl group generally employed inthe field of organic synthesis. Such protective groups include, forexample, (A) a group which forms an ether bond with an oxygen atom, (B)a group which forms an ester bond with an oxygen atom, (C) a group whichforms a carbonate with an oxygen atom and (D) a group which forms asulfonic acid ester with an oxygen atom.

Examples of the group (A) which forms an ether bond with an oxygen atominclude (1) an optionally substituted lower alkyl group, (2) anoptionally substituted allyl group, (3) an optionally substitutedcycloalkyl group, (4) an optionally substituted heterocyclic group, (5)an optionally substituted aralkyl group and (6) an optionallysubstituted silyl group.

The optionally substituted lower alkyl group (1) includes, for example,(a) an optionally substituted alkyl group having 1 to 4 carbon atomssuch as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl andt-butyl groups. The substituents for the C₁₋₄ alkyl group include, forexample, a C₁₋₄ alkoxy group, a C₁₋₄ alkoxy-C₁₋₄ alkoxy group, a C₇₋₂₀aralkyloxy group, a benzoyl group, a C₁₋₄ alkylthio group and a halogenatom and so on. Examples of such substituted C₁₋₄ alkyl group include(b) a C₁₋₄ alkoxy-C₁₋₄ alkyl group such as methoxymethyl, ethoxymethyl,t-butoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, 2-methoxyethyl(especially a C₁₋₄ alkoxy-C₁₋₂ alkyl group); (c) an C₁₋₄ alkoxy-C₁₋₄alkoxy-C₁₋₄ alkyl group such as 2-methoxyethoxymethyl,2-ethoxymethoxymethyl and the like (specifically a C₁₋₄ alkoxy-C₁₋₄alkoxy-C₁₋₂ alkyl group) ; (d) a C₇₋₂₀ aralkyloxy-C₁₋₄ alkyl group suchas benzyloxymethyl (especially, a C₇₋₂₀ aralkyloxymethyl group); (e) aphenacyl group; (f) a C₁₋₄ alkylthio-C₁₋₄ alkyl group such asmethylthiomethyl, ethylthiomethyl (specifically a C₁₋₄ alkylthiomethylgroup); and (g) a C₁₋₄ haloalkyl group having one or more of halogenatoms such as trichloromethyl, trifluoromethyl, 2,2,2-trichloroethyl,2,2,2-trifluoroethyl and the like.

The optionally substituted allyl group (2) includes, for instance, anallyl group. Examples of the optionally substituted cycloalkyl group (3)include a cycloalkyl group having 3 to 10 carbon atoms such ascyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl and cyclodecyl.

As the optionally substituted heterocyclic group (4), there may bementioned, for example, an optionally substituted 5- to 6-memberedheterocyclic group having an oxygen atom or a sulfur atom as a heteroatom. The optionally substituted heterocyclic group may frequently be aperhydroheterocyclic group. The 5- to 6-membered heterocyclic groupincludes, for instance, tetrahydrofuranyl, tetrahydrothiofuranyl,tetrahydropyranyl and tetrahydrothiopyranyl. Examples of the sustituentfor the heterocyclic group include a halogen atom, a C₁₋₄ alkyl group, aC₁₋₄ alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, s-butoxy and t-butoxy, and others as mentioned above.Practical examples of the optionally substituted heterocyclic groupinclude an optionally substituted tetrahydropyranyl group (e.g.tetrahydropyranyl, 3-bromotetrahydropyranyl, 4-methoxytetrahydropyranyl,etc.), an optionally substituted tetrahydrothiopyranyl group (forexample, tetrahydrothiopyranyl, 3-bromotetrahydrothiopyranyl,4-methoxytetrahydrothiopyranyl, etc.), an optionally substitutedtetrahydrofuranyl group (for instance, tetrahydrofuranyl, etc.), and anoptionally substituted tetrahydrothiofuranyl group (e.g.tetrahydrothiofuranyl).

Examples of the optionally substituted aralkyl group (5) include anoptionally substituted aralkyl group having 7 to 20 carbon atoms (e.g.benzyl, etc.). The substituent for the aralkyl group includes, forinstance, a C₁₋₄ alkyl group; a halogen atom; a nitro group; a C₁₋₄alkoxy group; a C₆₋₁₂ aryl group such as phenyl. Examples of suchsubstituent may be referred to those in above group (4). Typicalexamples of the optionally substituted aralkyl group include anoptionally substituted C₇₋₂₀ aralkyl group such as benzyl,o-chlorobenzyl, o-nitrobenzyl, p-chlorobenzyl, p-methoxybenzyl,p-methylbenzyl, p-nitrobenzyl, 2,6-dichlorobenzyl, diphenylmethyl,trityl and the like.

The substituent for the silyl group (6) includes a C₇₋₂₀ aralkyl groupsuch as benzyl group and substituents as mentioned in the aralkyl group(5). Examples of the optionally substituted silyl group (6) includetrimethylsilyl, triethylsilyl, t-butyldimethylsilyl, tribenzylsilyl,triphenylsilyl and so on.

As the group (B) which forms an ester bond with an oxygen atom, theremay be mentioned, for example, an optionally substituted acyl groupincluding (1) an optionally substituted acyl group having 1 to 6 carbonatoms such as formyl, acetyl, chloroacetyl, trifluoroacetyl, propionyl,isopropionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and thelike; (2) an optionally substituted C₇₋₁₆ acyl group having an aromaticring such as benzoyl, p-phenylbenzoyl, toluoyl, naphthoyl and others;(3) an optionally substituted acyl group having a heterocyclic ring suchas furoyl, thenoyl, nicotinoyl and isonicotinoyl groups.

The group (C) which forms a carbonate with an oxygen atom includes, forinstance, (1) an optionally substituted C₂₋₅ alkoxycarbonyl group suchas methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl andt-butoxycarbonyl; (2) an optionally substituted C₈₋₂₀ aralkyloxycarbonylgroup such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl,p-methylbenzyloxycarbonyl, p-chlorobenzyloxycarbonyl,o-nitrobenzyloxycarbonyl, etc.; (3) an optionally substituted C₇₋₂₀aryloxycarbonyl group such as phenoxycarbonyl,4-methylphenyloxycarbonyl, 4-nitrophenyloxycarbonyl,4-chlorophenyloxycarbonyl, naphthyloxycarbonyl and so on.

Examples of the group (D) which forms a sulfonic acid ester with anoxygen atom include (1) an optionally substituted alkylsulfonyl groupsuch as an optionally substituted C₁₋₄ alkylsulfonyl group (e.g.methanesulfonyl, ethanesulfonyl, trichloromethanesulfonyl,trifluoromethanesulfonyl, etc.); (2) an optionally substitutedarylsulfonyl group including an optionally substituted C₆₋₂₀arylsulfonyl group such as benzenesulfonyl, m-nitrobenzenesulfonyl,p-nitrobenzenesulfonyl, p-chlorobenzenesulfonyl, p-bromobenzenesulfonyl,p-toluenesulfonyl, naphthalenesulfonyl and others.

Preferred examples of R¹ and R² exemplified above include (i) a hydrogenatom; (ii) among the protective groups for hydroxyl group, (A) a groupwhich forms an ether bond with an oxygen atom, specifically, anoptionally substituted C₁₋₄ alkyl group and an optionally substitutedC₇₋₂₀ aralkyl group, and more specifically a C₁₋₄ alkyl group, and (B) agroup which forms an ester bond with an oxygen atom, especially a C₁₋₆acyl group (e.g. acetyl, etc.).

Where R¹ and R², in incorporation, form a ring together with theadjacent oxygen atoms, the ring may for example be a 5- to 10-memberedring, preferably a 5- to 8-membered ring and more preferably a 5- or6-membered ring. Such R¹ and R² includes, for instance, an optionallysubstituted alkylene group, a carbonyl group, a thiocarbonyl group andothers.

As the alkylene group, there may be mentioned, for instance, an alkylenegroup having 1 to 4 carbon atoms such as methylene, ethylene,trimethylene and the like. Preferred alkylene group includes a methylenegroup.

The optionally substituted methylene group includes, for example, agroup shown by the following formula (IX)

wherein R^(a) and R^(b) represent, (i) the same or different, a hydrogenatom, a C₁₋₄ alkyl group, a C₁₋₄ haloalkyl group, an optionallysubstituted C₆₋₂₀ aryl group, a C₁₋₄ alkoxy group, an optionallysubstituted amino group, a carboxyl group or a salt thereof, anoptionally substituted alkoxycarbonyl group, a hydroxymethyl group or anoptionally substituted alkoxymethyl group, or (ii) R^(a) and R^(b) mayform a C₅₋₇ cycloalkyl group together with the adjacent carbon atom.

The C₁₋₄ alkyl group, the C₁₋₄ haloalkyl group and the C₁₋₄ alkoxy groupin R^(a) and R^(b) include those exemplified in R¹ and R². Theoptionally substituted C₆₋₂₀ aryl group in R^(a) and R^(b) includes, forinstance, phenyl, 4-methoxyphenyl, 2-nitrophenyl and others. As thesubstituted amino group, there may be mentioned, for example, a mono- ordi-C₁₋₄ alkylamino group such as methylamino, dimethylamino, ethylamino,diethylamino and others.

As the salt of the carboxyl group represented by R^(a) and R^(b), anysalt can be employed. A salt which is pharmacologically acceptable mayfrequently be used. Examples of such salt include a salt with aninorganic base such as an alkali metal salt (e.g. a sodium salt or apotassium salt), an alkaline earth metal salt (for instance, a magnesiumsalt, a calcium salt or a barium salt), a metal salt (e.g. a zinc saltor an aluminum salt) and an ammonium salt; a salt with an organic basesuch as a salt with pyridine, a tri-C₁₋₃ alkylamine (e.g.trimethylamine, triethylamine, etc.) and so on.

The optionally substituted alkoxycarbonyl group in R^(a) and R^(b)includes, for instance, an optionally substituted C₂₋₅ alkoxycarbonylgroup as mentioned in R¹ and R².

As examples of the optionally substituted alkoxymethyl group in R^(a)and R^(b), there may be mentioned an optionally substituted a C₁₋₄alkoxy-methyl group which may be substituted on the alkyl with asubstituent. Such substituent for the alkoxymethyl group include, forexample, a carboxyl group, a C₂₋₅ alkoxycarbonyl group, a hydroxyl groupand a C₁₋₄ alkoxy group. The C₂₋₅ alkoxycarbonyl group and the C₁₋₄alkoxy group can be referred to the groups as mentioned in R¹ and R².Typical examples of the optionally substituted alkoxymethyl groupinclude (a) a C₁₋₄ alkoxy-methyl group such as methoxymethyl,ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxyemthyl,isobutoxymethyl, s-butoxymethyl and t-butoxymethyl; (b) a carboxy-C₁₋₄alkoxy-methyl group such as carboxymethoxymethyl, carboxyethoxymethyl,carboxypropoxymethyl, carboxybutoxymethyl, etc.; (c) a C₂₋₅alkoxycarbonyl-C₁₋₄ alkoxy-methyl group such asmethoxycarbonylmethoxymethyl, ethoxycarbonylmethxoymethyl,isopropoxycarbonylmethoxymethyl, 2-butoxycarbonylethoxymethyl andothers; (d) a hydroxy-C₁₋₄ alkoxy-methyl group such as2-hydroxyethoxymethyl, 3-hydroxypropoxymethyl and the like; (e) a C₁₋₄alkoxy-C₁₋₄ alkoxy-methyl group such as 2-methoxyethoxymethyl,2-ethoxyethoxymethyl, 3-methoxypropoxymethyl and so on.

The C₅₋₇ cycloalkyl group includes cyclopentyl, cyclohexyl andcycloheptyl groups.

As preferred examples of the optionally substituted methylene groupshown by the formula (IX), there may be mentioned, for instance, (a) thegroup of the formula (IX) wherein R^(a) and R^(b) are, the same ordifferent, a hydrogen atom, a C₁₋₄ alkyl group or a C₅₋₇ cycloalkylgroup formed with R^(a), R^(b) and the adjacent carbon atom (e.g. amethylene group, a C₂₋₄ alkylidene group such as an ethylidene group andan isopropylidene group; a C₅₋₇ cycloalkylidene group such as acyclopentylidene and a cyclohexylidene, and so on); (b) the group of theformula (IX) where R^(a) and R^(b) are respectively a carboxyl group ora salt thereof, an optionally substituted alkoxycarbonyl group, ahydroxymethyl group or an optionally substituted alkoxymethyl group.Specifically preferred is the group of the formula (IX) where R^(a) andR^(b) are, the same or different, a carboxyl group or a salt thereof, ora C₂₋₅ alkoxycarbonyl group.

Practically preferred examples of R¹ and R² include, a hydrogen atom, aC₁₋₄ alkyl group (particularly a methyl group), the optionallysubstituted methylene group of the formula (IX) formed by incorporationof R¹ and R² where R^(a) and R^(b) are respectively a carboxyl group ora salt thereof, or a C₂₋₅ alkoxycarbonyl group.

Examples of the lower alkyl group in R³, R⁴ and R⁵ include a C₁₋₄ alkylgroup as exemplified in R¹ and R².

The lower haloalkyl group in R³, R⁴ and R⁵ includes, for instance, ahaloalkyl group having 1 to 4 carbon atoms and one or more of halogenatoms such as chloromethyl, 2-chloroethyl, 4-chlorobutyl,trichloromethyl, trifluoromethyl and 1,1,2,2,2-pentafluoroethyl groups.As examples of the lower alkoxy group and the halogen atom, there may bementioned a C₁₋₄ alkoxy group and halogen atoms as mentioned in theexplanation of R¹ and R².

Preferred substituents of R³, R⁴ and R⁵ include, for example, a hydrogenatom and a lower alkyl group, especially a hydrogen atom.

The protective group of hydroxyl group in X as mentioned above includesan protective group for an alcoholic hydroxyl group usually or generallyused in the field of organic synthesis. Examples of such protectivegroup include the protective groups (A) to (C) as mentioned in theprotective groups for a hydroxyl group in R¹ and R².

The halogen atom in X includes the halogen atoms mentioned above.

Examples of the optionally substituted alkylsulfonyloxy group in Xinclude an optionally substituted C₁₋₄ alkylsulfonyloxy group such asmethanesulfonyloxy, ethanesulfonyloxy, trichloromethanesulfonyloxy andtrifluoromethanesulfonyloxy groups.

As examples of the optionally substituted arylsulfonyloxy group, theremay be mentioned an optionally substituted C₆₋₂₀ arylsulfonyloxy groupsuch as benzensulfonyloxy, m-nitrobenzenesulfonyloxy,p-nitrobenzenesulfonyloxy, p-chlorobenzenesulfonyloxy,p-bromobenzenesulfonyloxy, p-toluenesulfonyloxy, naphthalenesulonyloxyand others.

Typical examples of X include a hydroxyl group and a group which playsas a leaving group in a replacement reaction such as an optionallysubstituted C₁₋₄ alkylsulfonyloxy group, an optionally substituted C₆₋₂₀arylsulfonyloxy group, a halogen atom and the like. Particularly, ahydroxyl group; an optionally substituted alkylsulfonyloxy group having1 or 2 carbon atoms such as methanesulfonyloxy group; an optionallysubstituted arylsulfonyloxy group having 6 to 15 carbon atoms such asp-toluenesulfonyloxy group; chlorine atom, bromine atom and iodine atomare preferable.

In the (S)-1-phenyl-2-substituted propane derivative of the generalformula (I), preferred examples include compounds where R¹ and R² are,the same or different, (i) a hydrogen atom, a C₁₋₄ alkyl group(specifically a methyl group) or (ii) R¹ and R² incorporatively form anoptionally substituted methylene group of the formula (IX) wherein R^(a)and R^(b) are respectively a carboxyl group or a salt thereof, or a C₂₋₅alkoxycarbonyl group; R³, R⁴, and R⁵ are independently a hydrogen atomor a C₁₋₄ alkyl group; and X is a hydroxyl group, a C₁₋₂alkylsulfonyloxy group; a C₆₋₁₅ arylsulfonyloxy group or a halogen atom.

Practical examples of the (S)-1-phenyl-2-substituted propane derivativeshown by the general formula (I) include (1) an(S)-1-(3,4-dihydroxyphenyl)-2-substituted propane derivative, (2) an(S)-1-(3,4-di-C₁₋₄ alkoxyphenyl)-2-substituted propane derivative, (3)an (S)-1-(2,2-di-C₁₋₄ alkyl-1,3-benzodioxol-5-yl)-2-substituted propanederivative, (4) an (S)-1-[2,2-bis(C₂₋₅alkoxycarbonyl)-1,3-benzodioxol-5-yl]-2-substituted propane derivativeand (5) an (S)-1-(2,2-dicarboxy-1,3-benzodioxol-5-yl)-2-substitutedpropane derivative.

As the (S)-1-(3,4-dihydroxyphenyl)-2-substituted propane derivative (1),there may be mentioned, for instance,(S)-1-(3,4-dihydroxyphenyl)-2-propanol,(S)-[2-(3,4-dihydroxyphenyl)-1-methylethyl p-toluenesulfonate],(S)-[2-(3,4-dihydroxyphenyl)-1-methylethyl methanesulfonate],(S)-2-chloro-1-(3,4-dihydroxyphenyl)propane,(S)-2-bromo-1-(3,4-dihydroxyphenyl)propane and the like.

Examples of the (S)-1-(3,4-di-C₁₋₄ alkoxyphenyl)-2-substituted propanederivative (2) include (S)-1-(3,4-dimethoxyphenyl)-2-propanol,(S)-[2-(3,4-dinmethoxyphenyl)-1-methylethyl p-toluenesulfonate],(S)-[2-(3,4-dimethoxyphenyl)-1-methylethyl methanesulfonate],(S)-2-chloro-1-(3,4-dimethoxyphenyl)propane,(S)-2-bromo-1-(3,4-dimethoxyphenyl)propane and so on.

The (S)-1-(2,2-di-C₁₋₄ alkyl-1,3-benzodioxol- 5-yl)-2-substitutedpropane derivative (3) includes, for example,(S)-1-(2,2-dimethyl-1,3-benzodioxol-5-yl)-2-propanol,(S)-[1-methyl-2-(2,2-dimethyl-1,3-benzodioxol-5-yl)ethylp-toluenesulfonate],(S)-[1-methyl-2-(2,2-dimethyl-1,3-benzodioxol-5-yl)ethylmethanesulfonate],(S)-2-chloro-1-(2,2-dimethyl-1,3-benzodioxol-5-yl)propane,(S)-2-bromo-1-(2,2-dimethyl-1,3-benzodioxol-5-yl)propane, etc.

As examples of the (S)-1-[2,2-bis(C₂₋₅alkoxycarbonyl)-1,3-benzodioxol-5-yl]-2-substituted propane derivative(4), there may be mentioned (S)-[dimethyl5-(2-hydroxypropyl)-1,3-benzodioxole-2,2-dicarboxylate], (S)-[diethyl5-(2-hydroxypropyl)-1,3-benzodioxole-2,2-dicarboxylate], (S)-[dimethyl5-[2-(p-toluenesulfonyloxy)propyl]-1,3-benzodioxole-2,2-dicarboxylate],(S)-[diethyl5-[2-(p-toluenesulfonyloxy)propyl]-1,3-benzodioxole-2,2-dicarboxylate],(S)-[dimethyl5-[2-(methanesulfonyloxy)propyl]-1,3-benzodioxole-2,2dicarboxylate],(S)-[diethyl5-[2-(methanesulfonyloxy)propyl]-1,3-benzodioxole-2,2-dicarboxylate],(S)-[dimethyl 5-(2-chloropropyl)-1,3-benzodioxole-2,2-dicarboxylate],(S)-[diethyl 5-(2-chloropropyl)-1,3-benzodioxole-2,2-dicarboxylate],(S)-[dimethyl 5-(2-bromopropyl)-1,3-benzodioxole-2,2-dicarboxylate],(S)-[diethyl 5-(2-bromopropyl)-1,3-benzodioxole-2,2-dicarboxylate] andthe like.

Examples of the (S)-1-(2,2-dicarboxy-1,3-benzodioxol-5-yl)-2-substitutedpropane derivative (5) include (S)-[disodium5-[2-(hydroxypropyl)-1,3-benzodioxole-2,2-dicarboxylate], (S)-[disodium5-[2-(p-toluenesulfonyloxy)propyl]-1,3-benzodioxole-2,2-dicarboxylate],(S)-[disodium5-[2-(methanesulfonyloxy)propyl]-1,3-benzodioxole-2,2-dicarboxylate],(S)-[disodium 5-(2-chloropropyl)-1,3-benzodioxole-2,2-dicarboxylate],(S)-[disodium 5-(2-bromopropyl)-1,3-benzodioxole-2,2-dicarboxylate] andothers.

The (S)-1-phenyl-2-substituted propane derivative of the general formula(I) can be prepared by a variety of methods, for instance, by a chemicalreaction, and can advantageously be prepared by utilizing an action of amicroorganism or a preparation thereof.

Among the (S)-1-phenyl-2-substituted propane derivatives shown by thegeneral formula (I), (a) the compound wherein X is a hydroxyl group,that is, (S)-1-phenyl-2-propanol derivative shown by the general formula(III) can easily be obtained by asymmetrical reduction of thephenylacetone derivative shown by the general formula (II), (i) with theuse of a microorganism or a preparation thereof, or (ii) in a chemicalmethod, and harvesting or recovering the product (S)-1-phenyl-2-propanolderivative.

In the method (i), the (S)-1-phenyl-2-substituted propane derivative ofthe general formula (I) can be obtained by permitting a microorganism ora preparation thereof to act on the phenylacetone derivative of thegeneral formula (II) and harvesting or recovering the objective product.

The phenylacetone derivative of the general formula (II) used as a rawmaterial can easily be obtained by a conventional manner, for example,dry distillation of a mixture of an acetic acid salt such as an aceticacid salt with an alkaline earth metal (e.g. calcium acetate and bariumacetate) and a phenylacetic acid salt corresponding to the compound ofthe general formula (II) such as a phenyl acetic acid salt with analkaline earth metal salt (for instance, calcium phenylacetate, bariumphenylacetate, etc.) or others.

The microorganisms to be employed in accordance with the method may beany strain of microorganism that is capable of asymmetrically reducing aphenylacetone derivative shown by the general formula (II) to producethe optically active (S)-1-phenyl-2-substituted propane derivative shownby the general formula (III).

Examples of such microorganisms a strain of microorganism belonging tothe genus Sphingobacterium, the genus Aeromonas, the genusAgrobacterium, the genus Aureobacterium, the genus Bacillus, the genusCellulomonas, the genus Chromobacterium, the genus Corynebacterium, thegenus Gluconobacter, the genus Jensenia, the genus Comamonas, the genusPseudomonas, the genus Alternaria, the genus Amanita, the genusAspergillus, the genus Cochliobolus, the genus Corynespora, the genusDactylium, the genus Drechslera, the genus Echinopodospora, the genusGelasinospora, the genus Gonatobotryum, the genus Helminthosporium, thegenus Mortierella, the genus Paecilomyces, the genus Phialophora, thegenus Phytophthora, the genus Podospora, the genus Rhizomucor, the genusSeptoria, the genus Sporormielia, the genus Stemphylium, the genusTalaromyces, the genus Torula, the genus Ustilago, the genusWesterdykella, the genus Ambrosiozyma, the genus Dekkera, the genusCandida, the genus Clavispora, the genus Cryptococcus, the genusDebaryomryces, the genus Galactomyces, the genus Filobasidium, the genusGeotrichum, the genus Hansenula, the genus Issatchenkia, the genusKloeckera, the genus Kluyveromyces, the genus Leucosporidium, the genusLodderomyces, the genus Metschnikowia, the genus Myxozyma, the genusOosporidium, the genus Pachysolen, the genus Pichia, the genusMalassezia, the genus Rhodosporidium, the genus Kondoa, the genusRhodotorula, the genus Saccharomryces, the genus Octosporomyces, thegenus Sporidiobolus, the genus Sporobolomyces, the genusSporopachyderria, the genus Sterigmatomyces, the genus Torulaspora, thegenus Torulopsis, the genus Trigonopsis, the genus Wickerhamia, thegenus Wingea, the genus Zygoascus, the genus Zygosaccharomyces, thegenus Zygozyma and others.

(1) The strain of microorganism belonging to the genus Sphingobacteriumincludes Sphingobacterium sp. IFO 13310, etc.

(2) The strain of microorganism belonging to the genus Aeromonasincludes Aeromonas hydrophila subsp. proteolytiga IFO 13287, etc.

(3) The strain of microorganism belonging to the genus Agrobacteriumincludes Agrobacterium radiobacter IFO 12664, etc.

(4) The strain of microorganism belonging to the genus Aureobacteriumincludes Aureobacterium testaceum IFO 12675, etc.

(5) The strain of microorganism belonging to the genus Bacillus includesBacillus cereus AHU 1355, etc.

(6) The strain of microorganism belonging to the genus Cellulomonasincludes Cellulomonas flavigena IFO 3754, etc.

(7) The strain of microorganism belonging to the genus Chromobacteriumincludes Chromobacterium iodinum IFO 3558, etc.

(8) The strain of microorganism belonging to the genus Corynebacteriumincludes Corynebacterium aquaticum IFO 12154, etc.

(9) The strain of microorganism belonging to the genus Gluconobacterincludes Gluconobacter oxydans IFO 3255, etc.

(10) The strain of microorganism belonging to the genus Jenseniaincludes Jensenia canicruria IFO 13914, etc.

(11) The strain of microorganism belonging to the genus Comamonasincludes Comamonas acidovorans IFO 13582, etc.

(12) The strain of microorganism belonging to the genus Pseudomonasincludes Pseudomonas fluorescens IFO 3081, Pseudomonas putida IFO 3738,etc.

(13) The strain of microorganism belonging to the genus Alternariaincludes Alternaria japonica IFO 5244, etc.

(14) The strain of microorganism belonging to the genus Amanita includesAmanita citrina IFO 8261, etc.

(15) The strain of microorganism belonging to the genus Aspergillusincludes Aspergillus awamori nakazawa IFO 4033, Aspergillus ficuum IFO4018, Aspergillus niger AHU 7105, Aspergillus niger IFO 5374, etc.

(16) The strain of microorganism belonging to the genus Cochliobolusincludes Cochliobolus miyabeanus IFO 6631, etc.

(17) The strain of microorganism belonging to the genus Corynesporaincludes Corynespora casslicola IFO 6724, etc.

(18) The strain of microorganism belonging to the genus Dactyliumincludes Dactylium dendroides ATCC 46032, etc.

(19) The strain of microorganism belonging to the genus Drechsleraincludes Drechslera avenae IFO 6636, etc.

(20) The strain of microorganism belonging to the genus Echinopodosporaincludes Echinopodospora jamaicensis IFO 9819, etc.

(21) The strain of microorganism belonging to the genus Gelasinosporaincludes Gelasinospora cerealis IFO 6759, etc.

(22) The strain of microorganism belonging to the genus Gonatobotryumincludes Gonatobotryum apiculatum IFO 9098, etc.

(23) The strain of microorganism belonging to the genus Helminthosporiumincludes Helminthosporium sigmoideum var. irregulare IFO 5273, etc.

(24) The strain of microorganism belonging to the genus Mortierellaincludes Mortierella isabeilina IFO 6336, etc.

(25) The strain of microorganism belonging to the genus Paecilomycesincludes Paecilomyces variotii IFO 4855, etc.

(26) The strain of microorganism belonging to the genus Phialophoraincludes Phialophora pedrosoi IFO 6071, etc.

(27) The strain of microorganism belonging to the genus Phytophthoraincludes Phytophthora capsici IFO 8386, etc.

(28) The strain of microorganism belonging to the genus Podosporaincludes Podospora carbonaria IFO 30294, etc.

(29) The strain of microorganism belonging to the genus Rhizomucorincludes Rhizomucor pusillus IFO 4578, etc.

(30) The strain of microorganism belonging to the genus Septoriaincludes Septoria glycines IFO 5294, etc.

(31) The strain of microorganism belonging to the genus Sporormieliaincludes Sporozrqielia isomnera IFO 8538, etc.

(32) The strain of microorganism belonging to the genus Stemphyliumincludes Stemphylium sarciniforme IFO 7243, etc.

(33) The strain of microorganism belonging to the genus Talarormycesincludes Talarormyces flavus var. flavus IFO 7231, etc.

(34) The strain of microorganism belonging to the genus Torula includesTorula jeanselmei IFO 6857, etc.

(35) The strain of microorganism belonging to the genus Ustilagoincludes Ustilago cynodontis IFO 7530, etc.

(36) The strain of microorganism belonging to the genus Westerdykeilaincludes Westerdykella multispora IFO 5813, etc.

(37) The strain of microorganism belonging to the genus Ambrosiozymaincludes Ambrosiozyma cicatricosa IFO 1846, Ambrosiozyma monospora IFO1965, etc.

(38) The strain of microorganism belonging to the genus Dekkera includesDekkera custersianus IFO 1585, etc.

(39) The strain of microorganism belonging to the genus Candida includesCandida aaseri IFO 10104, Candida atomspherica IFO 1969, Candida beechiiIFO 10229, Candida diversa IFO 1091, Candida ergatensis IFO 10233,Candida fluviatilis IFO 10234, Candida fusiformate IFO 10225, Candidaglabrata IFO 0622, Candida gropengiesseri IFO 0659, Candidahalonitratophila IFO 1595, Candida inconspicua IFO 0621, Candida kefyrDSM 70073, Candida krusei DSM 70075, Candida lambica DSM 70090, Candidamogii IFO 0436, Candida maltosa IFO 1978, Candida melibiosica IFO 10238,Candida membranaefaciens IFO 1246, Candida oleophila JCM 2444, Candidaparapsilosis IFO 1022, Candida pintolopesii var. pintolopesii IFO 0729,Candida pseudointermedia IFO 1693, Candida catenulata DSM 70136, Candidarugosa IFO 0591, Candida saitoana IFO 0768, Candida sake IFO 1149,Candida natalensis IFO 1981, Candida salmanticensis IFO 10242, Candidasantamariae IFO 1982, Candida schatavii IFO 10258, Candida shehatae IFO1983, Candida silvanorum IFO 10419, Candida sorbophila IFO 1583, Candidatenuis IFO 10315, Candida utilis IFO 0396, Candida utilis IFO 0988,Candida albicans IFO 0159, etc.

(40) The strain of microorganism belonging to the genus Clavisporaincludes Clavispora lusitaniae IFO 1019, etc.

(41) The strain of microorganism belonging to the genus Cryptococcusincludes Cryptococcus humicolus IFO 0760, Cryptococcus neoformans IAM4788, etc.

(42) The strain of microorganism belonging to the genus Debaryomycesincludes Debaryomyces varijiae DSM 70252, etc.

(43) The strain of microorganism belonging to the genus Galactomycesincludes Galactomyces reessli IFO 1112, etc.

(44) The strain of microorganism belonging to the genus Filobasidiumincludes Filobasidium capsuligenum IFO 1119, etc.

(45) The strain of microorganism belonging to the genus Geotrichumincludes Geotrichum candidum IFO 4598, Geotrichum fermentans JCM 2467,Geotrichum fragrans JCM 2450, etc.

(46) The strain of microorganism belonging to the genus Hansenulaincludes Hansenula polymorpha ATCC 26012, Hansenula capsulata DSM 70269,Hansenula glucozyma DSM 70271, Hansenula wickerhamii DSM 70280, etc.

(47) The strain of microorganism belonging to the genus Issatchenkiaincludes Issatchenkia scutulata var. scutulata IFO 10070, etc.

(48) The strain of microorganism belonging to the genus Kloeckeraincludes Kloeckera africana IFO 0869, etc.

(49) The strain of microorganism belonging to the genus Kluyveromycesincludes Kluyveromyces lactis IFO 0433, Kluyveromyces marxianus DSM70800, Kluyveromyces polysporus DSM 70294, etc.

(50) The strain of microorganism belonging to the genus Leucosporidiumincludes Leucosporidium scottii IFO 1924, etc.

(51) The strain of microorganism belonging to the genus Lodderomycesincludes Lodderomyces elongisporus IFO 1676, etc.

(52) The strain of microorganism belonging to the genus Metschnikowiaincludes Metschnikowia bicuspidata IFO 1408, Metschnikowia pulcherrimaDSM 70336, Metschnikowia reukaufii DSM 70880, etc.

(53) The strain of microorganism belonging to the genus Myxozymaincludes Myxozyma lipomycoides IFO 10350, etc.

(54) The strain of microorganism belonging to the genus Oosporidiumincludes Oosporidium margaritiferum IFO 1208, etc.

(55) The strain of microorganism belonging to the genus Pachysolenincludes Pachysolen tannophilus IFO 1007, etc.

(56) The strain of microorganism belonging to the genus Pichia includesPichia cellobiosa DSM 2147, Pichia farinosa IFO 1163, Pichia lindneriiDSM 70718, Pichia ohmeri DSM 70815, Pichia thermotolerans IFO 10025,Pichia pastoris DSM 70382, Pichia trehalophila DSM 70391, Pichiacarsonii DSM 70392, Pichia subpelliculosa IFO 0808, etc.

(57) The strain of microorganism belonging to the genus Malasseziaincludes Malassezia furfur IFO 0656, etc.

(58) The strain of microorganism belonging to the genus Rhodosporidiumincludes Rhodosporidium diobovatum IFO 1830, Rhodosporidium toruloidesIFO 1638, etc.

(59) The strain of microorganism belonging to the genus Kondoa includesKondoa malvinella IFO 1936, etc.

(60) The strain of microorganism belonging to the genus Rhodotorulaincludes Rhodotorula glutinis AHU 3454, Rhodotorula rubra IFO 0383, etc.

(61) The strain of microorganism belonging to the genus Saccharomycesincludes Saccharomyces rouxii IAM 0487, etc.

(62) The strain of microorganism belonging to the genus Octosporomycesincludes Octosporomyces octosporus IFO 0353, etc.

(63) The strain of microorganism belonging to the genus Sporidiobolusincludes Sporidiobolus johnsonii IFO 6903, Sporidiobolus pararoseus IFO1104, Sporidiobolus salmonicolor IFO 1845, etc.

(64) The strain of microorganism belonging to the genus Sporobolcmycesincludes Sporobolomyces pararoseus IFO 1036, etc.

(65) The strain of microorganism belonging to the genus Sporopachydermiaincludes Sporopachydermia lactativora IFO 1867, etc.

(66) The strain of microorganism belonging to the genus Sterigmatomycesincludes Sterigmatomyces elviae DSM 70852, etc.

(67) The strain of microorganism belonging to the genus Torulasporaincludes Torulaspora delbrueckii IFO 0381, etc.

(68) The strain of microorganism belonging to the genus Torulopsisincludes Torulopsis nemodendra DSM 70647, etc.

(69) The strain of microorganism belonging to the genus Trigonopsisincludes Trigonopsis variabilis IFO 0755, etc.

(70) The strain of microorganism belonging to the genus Wickerhamiaincludes Wickerhamia fluorescens DSM 70715, Wickerhamiella domercquiiIFO 1857, etc.

(71) The strain of microorganism belonging to the genus Wingea includesWingea robertsii IFO 1277, etc.

(72) The strain of microorganism belonging to the genus Zygoascusincludes Zygoascus hellenicus IFO 1575, etc.

(73) The strain of microorganism belonging to the genusZygosaccharomyces includes Zygosaccharomyces bailii IFO 0468,Zygosaccharomyces bisporus DSM 70415, etc.

(74) The strain of microorganism belonging to the genus Zygozymaincludes Zygozyma oligophaga IFO 10360, etc.

For the purposes of the invention, any of wild strains, mutants andrecombinant strains which can be obtained by a genetic engineeringtechnique such as cell fusion or gene manipulation can suitably be used,as far as having the above mentioned ability or capability.

The microorganisms identified hereinabove by IFO numbers are describedin the “List of Cultures Ed. 9” published by Institute for Fermentation,Osaka (IFO), Japan and are available from the same Institute. Themicroorganisms designated by JCM numbers are listed in “Catalogs ofMicrobial Strains Ed. 5 (1992)” published by the Culture Collection ofThe Institute of Physical and Chemical Research, Japan and availablefrom the same Culture Collection. The microorganism designated by DSMnumbers are listed in “Catalogue of strains (1989)” published by theDeutsch Sammlung von Mikroorganismen (DSM) and are available from thesame organization. The yeast identified by ATCC number (Hansenulapolymorpha ATCC 26012) is listed in “Catalogue of Yeasts, Ed. 18 (1990)”and the filamentous fungus designated by ATCC number (Dactyliumdedroides ATCC 46032) is listed in “Catalogue of Filamentous fungi, Ed.18 (1991)” each published by the American Type Culture Collection (ATCC)and are respectively available from the same organization. Themicroorganisms titled by IAM numbers are available from Institute ofApplied Microbiology, Tokyo University, Japan. The microorganismsidentified by AHU numbers are available from Faculty of Agriculture,Hokkaido University, Japan.

The medium which is used for growing the strain for use in the inventionis not critical in composition only if the selected strain may grow andmultiply therein. The medium may frequently be a fluid medium containingsources of carbon and nitrogen and other nutrients. Any carbon sourcewhich the strain can utilize may be employed. As the sources of carbon,there may be employed various carbohydrates or saccharides such asglucose, fructose, sucrose, dextrin, starch, etc.; alcohols such assorbitol, methanol, ethanol, glycerol, etc.; organic acids such asfumaric acid, citric acid, acetic acid, propionic acid, etc. and thecorresponding salts; hydrocarbons such as paraffin; and various mixturesthereof. The sources of nitrogen include, for instance, inorganic acidammonium salts such as ammonium chloride, ammonium sulfate, ammoniumphosphate, etc.; organic acid ammonium salts such as ammonium fumarate,ammonium citrate, etc.; inorganic or organic nitrogen-containingmaterials such as meat extract, yeast extract, malt extract, peptone(polypeptone), corn steep liquor, casein hydrolysate, urea, etc.; andvarious mixtures thereof.

In the medium, there may be incorporated appropriate amounts ofL thosenutrients which are commonly employed in the cultivation ofmicroorganisms, such as inorganic salts, trace metal salts and vitamins.Where necessary, there may also be incorporated factors which maypromote growth of the strain used and/or factors which may augment itsability to produce the object compound of the invention, as well as abuffer substance which may assist in the maintenance of the medium at agiven pH.

The cultivation of the microorganism is carried out under conditionsoptimal for the growth of the particular strain, for example at a mediumpH in the range of about 2.0 to 9.5, preferably about 3 to 8, and anincubation temperature in the range of about 20 to 45° C., preferablyabout 25 to 37° C. The cultivation may be aerobic or anaerobic. Thecultivation time is, for example, about 5 to 120 hours, preferably about12 to 72 hours.

The method of asymmetric reduction is not critical so far as thefunction of a microorganism or a preparation thereof is acted on thephenylacetone derivative of the general formula (II) to produce the(S)-1-phenyl-2-substituted propane derivative of the general formula(I), and may, for example, be whichever of the following alternatives:(1) a technique adding the phenylacetone derivative to the culturemedium where the microorganism is cultivated, (2) a technique adding ormixing the phenylacetone derivative with a culture broth as such toconduct the reaction, (3) a technique which comprises separating themicrobial cells from the culture broth, e.g. by centrifugation,resuspending the cells, either as they are or after washing, in a buffersolution, water or the like, and adding the phenylacetone derivative tothe resulting cell suspension to treat the mixture therewith.

There are cases in which this reaction proceeds with advantage of ahigher yield of the objective optically active compound in the presenceof a carbon source such as glucose, sucrose, ethanol, methanol orparaffin which serves as an energy source.

In the reaction, wet viable cells as such can be used, or a treatedpreparation of cells such as disrupted cells, acetone-treated cells,lyophilized cells can also be employed. These cells or preparationthereof can be employed as immobilized by known techniques such as thepolyacrylamide gel method, sulfur-containing polysaccharide gel method(e.g. carrageenin gel method), alginic acid gel method, agar gel methodand so on. The enzyme purified from such a cell preparation can also beused. The enzyme can be obtained with the use of known purificationprocesses in a suitable combination.

The corresponding phenylacetone derivative can be used as it is or inthe form of a solution, suspension or dispersion containing a suitablesolvent. As the solvent, water or an organic solvent which will notinterfere with the reaction can be employed. A suspension or adispersion prepared with a surfactant can also be used when necessary.The phenylacetone derivative may be added in bolus at the beginning ofthe reaction or in several installments.

The optimal cell concentration of the reaction system can be selectedfrom the range where the yield and the optical purity of the desiredoptically active compound will not be adversely affected. A typical cellconcentration may for example be, on a dry cell basis, about 0.1 to 500g/liter and preferably about 1 to 300 g/liter. The concentration of thesubstance phenylacetone derivative is not particularly restricted andis, for example, about 0.01 to 20% by weight and preferably about 0.1 to10% by weight.

The reaction conditions of the asymmetric reduction can be selected fromthe ranges that will not detract from the yield of the object compound.For example, the pH of the reaction system can be selected from therange of pH about 2 to 10 and preferably pH about 3 to 8. The reactiontemperature is selected from the range of, for example, about 10 to 60°C. and preferably from about 20 to 40° C. and more preferably from about20 to 35° C. The reaction can be conducted with stirring or understationary conditions for about 1 to 120 hours.

Thus, when permitting the microorganism or a preparation thereof to acton the phenylacetone derivative, the asymmetric reduction can proceedsmoothly or advantageously to produce the corresponding1-phenyl-2-propanol derivative having an (S)-configuration with a highselectivity.

The (S)-1-phenyl-2-propanol derivative of the general formula (III)produced by the reaction can be recovered or harvested by the separationand purification procedures generally known. For example, the(S)-1-phenyl-2-propanol derivative having a high optical purity can beeasily obtained by subjecting the reaction mixture, directly or afterseparation of the cells, to the conventional purification procedure suchas membrane separation, extraction with an organic solvent,crystallization, recrystallization, column chromatography, vacuumconcentration and distillation. The optical purity of optically activecompound can be measured by high performance liquid chromatography(HPLC) using an optical resolution column.

In the (S)-1-phenyl-2-substituted propane derivatives shown by thegeneral formula (I), (b) the compound wherein X is an optionallysubstituted alkylsulfonyloxy group, an optionally substitutedarylsulfonyloxy group or a halogen atom, that is a compound shown by thegeneral formula (IV), can easily or readily be obtained from thecompound of the formula (III) by selecting an reagent, for example asulfonylating agent or a halogenating agent, a catalyst and reactionconditions from the range where the reaction proceeds with retention instereochemistry. Such reaction is illustrated, for instance, by thefollowing scheme:

The sulfonylating agent includes a variety of conventional sulfonylatingagents which can convert a hydroxyl group into an alkylsulfonyloxy orarylsulfonyloxy group, for example, an optionally substitutedalkylsulfonyl halide or an optionally substituted arylsulfonyl halide.

As the optionally substituted alkylsulfonyl halide and the optionallysubstituted arylsulfonyl halide, those corresponding to X may beemployed. Such optionally substituted alkylsulfonyl halide include, forinstance, an alkylsulfonyl halide having 1 to 4 carbon atoms which maybe substituted with a substituent such as a halogen atom on the alkylgroup, including methanesulfonyl chloride, methanesulfonyl bromide,ethanesulfonyl chloride, ethanesulfonyl bromide,trichloromethanesulfonyl chloride, trifluoromethanesulfonyl chloride,and the like. Examples of the optionally substituted arylsulfonyl halideinclude an arylsulfonyl halide having 6 to 20 carbon atoms, preferably 6to 15 carbon atoms, which may have a substituent such as an alkyl group,a nitro group and a halogen atom on the aromatic ring, for example,benzenesulfonyl chloride, benzenesulfonyl bromide, o-toluenesulfonylchloride, p-toluenesulfonyl chloride, p-toluenesulfonyl bromide,m-nitrobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride,p-chlorobenzenesulfonyl chloride, p-bromobenzenesulfonyl chloride,naphthalenesulfonyl chloride and so on.

The reaction of the (S)-1-phenyl-2-propanol derivative of the generalformula (III) with the sulfonylating agent can be carried out, usuallyin the presence of a base at a temperature of, for instance, about −20°C. to 100° C., preferably about −10° C. to 40° C., and more preferablyabout 0° C. to 30° C. When the reaction temperature is lower than −20°C., the reaction rate is decreased, and when the reaction temperatureexceeds 100° C., occurrence of a side reaction tends to be enhanced.

The base includes inorganic bases and organic bases. As examples of theinorganic bases, there may be mentioned alkali metal hydroxides such assodium hydroxide, potassium hydroxide and lithium hydroxide; alkalineearth metal hydroxides such as magnesium hydroxide, calcium hydroxideand barium hydroxide; alkali metal carbonates such as sodium carbonate,potassium carbonate and lithium carbonate; alkaline earth metalcarbonate such as magnesium carbonate, calcium carbonate and bariumcarbonate; alkali metal hydrogencarbonates such as sodiumhydrogencarbonate and potassium hydrogencarbonate. The organic basesinclude, for example, metal alkoxides such as alkali metal alkoxides(for example, a sodium or potassium C₁₋₄ alkoxide such as sodiummethoxide, sodium ethoxide, sodium propoxide, sodium butoxide, potassiummethoxide, potassium ethoxide, potasium propoxide and potasium butoxide,etc.); primary amines such as an alkylamine (e.g. a C₁₋₈ alkylamine suchas methylamine, ethylamine, propylamine, butylamine, etc.); secondaryamines such as chain amines including an dialkylamine (e.g. a di-C₁₋₈alkylamine such as dimethylamine, diethylamine, dipropylamine,diisopropylamine, dibuthylamine, diisobutylamine, di-s-butylamine,di-t-butylamine, dipentylamine, dihexylamine, diheptylamine,dioctylamine, etc.), and cyclic amines such as pipecoline, piperidine,morpholine, pyrrolidine, etc.; tertiary amines such as a trialkylamine(e.g. a tri-C₁₋₈ alkylamine such as trimethylamine, triethylamine,tripropylamine, tributylamine, etc.), alkanolamines such as N,N-di-C₁₋₄alkyl alkanolamine (e.g. N,N-dimethylethanolamine, and the like),N,N-dimethylaniline, 4-dimethylaminopyridine, N-methylmorpholine,N-methylpiperidine, and others; nitrogen-containing heterocycriccompounds such as pyridine, quinoline, picoline, and others. As thebase, the organic bases such as pyridine may frequently be employed.

The reaction may be conducted in an inert solvent. As the solvent, theremay be mentioned, for instance, aromatic hydrocarbons such as benzene,toluene, xylene and ethylbenzene; aliphatic hydrocarbons such aspentane, hexane, heptane and octane; alicyclic hydrocarbons such ascyclohexane and methylcyclohexane; halogenated hydrocarbons such ascarbon tetrachloride, chloroform, dichloromethane and1,2-dichloroethane; ethers such as diethyl ether, dibutyl ether, dioxaneand tetrahydrofuran; ketones such as acetone and methyl ethyl ketone;esters such as methyl acetate and ethyl acetate; aprotic polar solventssuch as acetonitrile, N,N-dimethylformamide and dimethyl sulfoxide.

The using amount of the sulfonylating agent can be selected from asuitable range depending on the reaction rate and economic factors, andis usually about 0.9 gram equivalent or more, preferably about 0.9 to1.5 gram equivalents and more preferably about 1.1 to 1.3 gramequivalents, relative to 1 gram equivalent of the(S)-1-phenyl-2-propanol derivative of the general formula (III).

By the reaction of the (S)-phenyl-2-propanol derivative with thesulfonylating agent, the corresponding(S)-2-alkylsulfonyloxy-1-phenylpropane derivative or(S)-2-arylsulfonyloxy-1-phenylpropane derivative can selectively beproduced with a good yield.

As the halogenating agent, there may be mentioned, for instance,conventional halogenating agents usable when halogenating an opticallyactive alcohol wherein a hydroxyl group is bonded to an asymmetriccarbon with retention of the configuration. Examples of suchhalogenating agents include thionyl chloride, thionyl bromide and thelike.

The reaction of the (S)-1-phenyl-2-propanol derivative with thehalogenating agent can be carried out at a temperature of, for example,about −20° C. to 150° C. and preferably about 10° C. to 120° C. Thereaction conducted at a temperature lower than −20° C. decreases thereaction rate, and the reaction carried out at a temperature exceeding150° C. tends to cause a side reaction. The reaction may be conducted inan inert solvent. The solvent exemplified as above can also be used inthis reaction. The preferred solvent includes a solvent, whichadvantageously proceed the reaction with retention of the configuration,for example, a solvent containing an oxygen atom or a sulfur atom suchas ethers including, for instance, dioxane, diethyl ether, dipropylether, diisopropyl ether, 1,2-dimethoxyethane, anisole, tetrahydrofuran,and the like. The halogenating agent can also be used as the solvent.

The amount of the halogenating agent relative to 1 gram equivalent ofthe (S)-1-phenyl-2-propanol derivative of the general formula (III) is,for instance, about 0.9 gram equivalent or more and preferably about 0.9to 1.5 gram equivalents. In order to proceed the reaction smoothly, areaction accelerator such as sodium chloride, sodium bromide andN,N-dimethylformamide; the above mentioned base or the like can be addedto the reaction system.

By the reaction of the (S)-1-phenyl-2-propanol derivative of the generalformula (III) and the halogenating agent, the corresponding(S)-2-halo-1-phenylpropane derivative can selectively and efficiently beproduced.

The (S)-1-phenyl-2-substituted propane derivative of the general formula(IV) produced by the sulfonylation or halogenation as mentioned abovecan be recovered by conventional separation and purification procedures.For example, the (S)-1-phenyl-2-substituted propane derivative having ahigh optical purity can be easily obtained by subjecting the reactionmixture to the conventional purification procedure such as pH adjustmentor control of the reaction mixture, extraction with an organic solvent,crystallization, recrystallization, vacuum concentration, columnchromatography and distillation.

The (S)-1-phenyl-2-substituted propane derivative of the general formula(IV) thus obtained can advantageously be employed as an intermediate forsynthesis of the (R,R)-1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanolderivative usable as a medicinal compound or an intermediate thereof.

In the (S)-1-phenyl-2-substituted propane derivatives of the generalformula (I), (c) other compounds than the compounds of the generalformula (III) or (IV), that is, the compounds wherein X is a hydroxylgroup which is protected by a protective group can readily or easily beobtained by protecting the hydroxyl group of the compound of the generalformula (II) with the protective group in accordance with a conventionalmanner using a protective reagent. The compound thus obtained canappropriately be used when the protection of the hydroxyl group isrequired in chemical reaction for producing another derivative from thecompound of the general formula (I).

In the (S)-1-phenyl-2-substituted propane derivatives of the generalformula (I) of the present invention, R¹, R² or both can be convertedfrom one substituent to another by a conventional technique.

For example, the (S)-1-phenyl-2-substituted propane derivative of thegeneral formula (I) where R¹ and R² are both methyl groups can easily beconverted to the compound where R¹ and R² incorporatively form the groupshown by the formula (IX) in accordance with the following scheme.

wherein R¹¹, R¹² and R¹³ respectively represent an optionallysubstituted alkyl group; X^(a) and X^(b) are independently a halogenatom; and R³, R⁴, R⁵ and X have the same meanings as defined above.

In the reaction, a compound of the formula (Ic) having the group of theformula (IX) where R^(a) and R^(b) are both optionally substitutedalkoxycarbonyl groups, can be prepared by allowing a demethylating agentsuch as BBr₃ to react with the compound of the general formula (I) whereR¹ and R² are both methyl groups, that is, the compound of the formula(Ia), and allowing a dihalomalonic acid ester shown by the formula (XI)such as diethyl dibromomalonate to react with the demethylated compoundof the formula (Ib) in the presence of a base such as potassiumcarbonate. The resultant compound (Ic) can be introduced to a compoundof the formula (Id) having the group of the formula (IX) where R^(a) andR^(b) are both hydroxyl groups by using a reducing agent such as lithiumborohydride. When allowing a halogenated alkyl of the formula (XII) toreact with the compound of the formula (Id) in the presence of a basesuch as sodium hydride, a compound of the formula (Ie) having the groupof the formula (XI) where R^(a) and R^(b) are respectively an optionallysubstituted alkoxymethyl group can be obtained.

Further, hydrolysis of the compound of the formula (Ic) in accordancewith a conventional hydrolyzing method such as alkali hydrolysis usingan alkali including an alkali metal hydroxide (e.g. sodium hydroxide) orthe like can easily or readily afford a compound of the formula (If)having the group of the formula (IX) wherein R^(a) and R^(b) are, thesame or different, a carboxyl group or a salt thereof.

With regard to the method, the disclosures and descriptions in the abovementioned U.S. Pat. No. 5,061,727 and J. Med. Chem., 35, 3081 (1992) canbe referred, and these disclosures and descriptions can be incorporatedwith the disclosure of the present specification.

The process for producing the(R,R)-1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol derivative shownby the general formula (VI) of the present invention is characterized byallowing the (R)-2-amino-1-phenylethanol derivative of the generalformula (V) to react with the (S)-1-phenyl-2-substituted propanederivative of the general formula (IV) with inversion in stereochemistryto produce the objective compound of the formula (VI).

The lower alkyl group, lower haloalkyl group, lower alkoxy group orhalogen atom in R⁶, R⁷, R⁸, R⁹ and R¹⁰ of the general formula (V) may bereferred to the lower alkyl group or the like exemplified above. As thesubstituent R⁹, a lower haloalkyl group such as a C₁₋₄ haloalkyl group,a halogen atom, a nitro group or the like, particularly a halogen atomsuch as chlorine atom is preferable. Preferred examples of R⁶, R⁷, R⁸and R¹⁰ include a hydrogen atom and a C₁₋₄ alkyl group, specifically ahydrogen atom.

The protective group for hydroxyl group in Z of the general formula (V)may refer to, for example, a group mentioned as the protective group forhydroxyl group in the explanation for R¹, R and X.

Typical examples of Z include a hydrogen atom, (A) a group which formsan ether bond with an oxygen atom, particularly, C₁₋₄ alkyl group, anoptionally substituted 5- to 6-membered heterocyclic group having anoxygen atom or a sulfur atom as a hetero atom, and an optionallysubstituted silyl group, (B) a group which forms an ester bond with anoxygen atom such as an optionally substituted C₁₋₆ acyl group, anoptionally substituted C₇₋₁₆ acyl group having an aromatic ring and anoptionally substituted acyl group having a heterocyclic ring, and (C) agroup which forms a carbonate with an oxygen atom such as an optionallysubstituted C₂₋₅ alkoxycarbonyl group, an optionally substituted C₈₋₂₀aralkyloxycarbonyl group and an optionally substituted C₇₋₂₀aryloxycarbonyl group. Particularly, a hydrogen atom can advantageouslybe used as Z.

In the present invention, the protective group for hydroxyl group,introduction of the protective group to hydroxyl group and cleavage ofthe protective group may, for example, be referred to and incorporatedwith “Protective Groups in Organic Synthesis” (T. W. Greene, AWiley-Interscience Publication, John Wiley & Sons (1981)).

As practical examples of the (R)-2-amino-1-phenylethanol derivativeshown by the general formula (V), there may be mentioned (a)(R)-2-amino-1-phenylethanol; (b) an (R)-2-amino-1-(3-nitrophenyl)ethanolderivative such as (P)-2-amino-1-(3-nitrophenyl)ethanol,(R)-2-amino-1-(2-methyl-3-nitrophenyl)ethanol, etc.; (c) an(R)-2-amino-1-(3-halophenyl)ethanol derivative such as(R)-2-amino-1-(3-chlorophenyl)ethanol,(R)-2-amino-1-(2,3-dichlorophenyl)ethanol,(R)-2-amino-1-(3,4-dichlorophenyl)ethanol,(R)-2-amino-1-(3-bromophenyl)ethanol,(R)-2-amino-1-(2,3-dibromophenyl)ethanol,(R)-2-amino-1-(3,4-dibromophenyl)ethanol, (R)-2-amino-1-(3-fluorophenyl)ethanol, (R)-2-amino-1-(2,3-difluorophenyl)ethanol,(R)-2-amino-1-(3,4-difluorophenyl)ethanol and the like; (d) an(R)-2-amino-1-(3-C₁₋₄ haloalkyl-phenyl)ethanol derivative such as(R)-2-amino-1-[3-chloromethylphenyl]ethanol,(R)-2-amino-1-[3-(2-chloroethyl)phenyl]ethanol,(R)-2-amino-1-[3-(4-chlorobutyl)phenyl]ethanol,(R)-2-amino-1-(3-trichloromethylphenyl)ethanol,(R)-2-amino-1-(3-trifluoromethylphenyl)ethanol,(R)-2-amino-1-[3-(1,1,2,2,2-pentafluoroethyl)phenyl]ethanol, etc.; (e)an (R)-2-amino-1-(3-C₁₋₄ alkoxy-phenyl)ethanol derivative such as(R)-2-amino-1-(3-methoxyphenyl)ethanol,(R)-2-amino-1-(3-methoxy-4-chlorophenyl)ethanol,(R)-2-amino-1-(3-methoxy-4-methylphenyl)ethanol,(R)-2-amino-1-(3-ethoxyphenyl)ethanol; (f) an (R)-2-amino-1-(3-C₁₋₄alkyl-phenyl)ethanol derivative such as(R)-2-amino-1-(3-methylphenyl)ethanol,(R)-2-amino-1-(3-ethylphenyl)ethanol, (R)-2-amino-1-(3-propylphenylethanol, (R)-2-amino-1-(3-t-butylphenyl)ethanol, etc.; (g) an(R)-2-amino-1-(2-substituted phenyl)ethanol derivative such as(R)-2-amino-1-(2-chlorophenyl)ethanol, (R)-2-amino-1-(2-bromophenyl)ethanol,(R)-2-amino-1-(2-fluorophenyl)ethanol,(R)-2-amino-1-(2-trifluoromethylphenyl) ethanol,(R)-2-amino-1-(2-methoxyphenyl)ethanol,(R)-2-amino-1-(2-ethoxyphenyl)ethanol,(R)-2-amino-1-(2-methylphenyl)ethanol,(R)-2-amino-1-(2-ethylphenyl)ethanol),(R)-2-amino-1-(2-propylphenyl)ethanol,(R)-2-amino-1-(2-t-butylphenyl)ethanol and the like; (h) an(R)-2-amino-1-(4-substituted phenyl)ethanol derivative such as(R)-2-amino-1-(4-chlorophenyl)ethanol,(R)-2-amino-1-(4-bromophenyl)ethanol,(R)-2-amino-1-(4-fluoropherlyl)ethanol,(R)-2-amino-1-(4-trifluoromethylphenyl)ethanol, (R)-2-amino-1-(4-methoxyphenyl)ethanol,(R)-2-amino-1-(4-ethoxyphenyl)ethanol,(R)-2-amino-1-(4-methylphenyl)ethanol,(R)-2-amino-1-(4-ethylphenylethanol),(R)-2-amino-1-(4-propylphenyl)ethanol,(R)-2-amino-1-(4-t-butylphenyl)ethanol, and so on.

The (R)-2-amino-1-phenylethanol derivative of the general formula (V)can be obtained by, for instance, subjecting the corresponding racemic2-amino-1-phenylethanol derivative to a conventional optical resolution.For example, the compound can readily be obtained by allowing anoptically active carboxylic acid such as an amino acid (e.g. D-alanine)derivative where the amino group is protected (e.g.N-(t-butoxycarbonyl)-D-alanine, etc.) to react with the racemicderivative to form a diastereomeric salt and recrystallizing theobjective compound from the salt. The racemic 2-amino-1-phenylethanolderivative can be prepared by a conventional manner, for instance,allowing a trialkylsilylcyanide such as trimethylsilylcyanide to reactwith the corresponding benzaldehyde derivative in the presence of aLewis acid such as anhydrous aluminum chloride to produce ano-trialkylsilylmandelonitrile derivative such aso-trimethylsilylmandelonitrile derivative, subjecting the resultantcompound to treatment with a reducing agent such as sodium borohydrideand to hydrolysis with an acid, and, when necessary, protecting thehydroxyl group with a suitable protective group.

The reaction of the compound of the general formula (V) and the compoundof the general formula (IV) can be carried out, by selecting a reagent,a catalyst and reaction conditions in a suitable range as far as thereaction can be proceeded with inversion of the configuration, and, forexample, at about 0 to 150° C. and preferably about 20 to 120° C. If thereaction temperature is lower than 0° C., the reaction rate isdecreased, and if it exceeds 150° C., a side reaction is liable tooccur.

The reaction may preferably be carried out in the presence of a base. Ause of the base may increase the optical purity of the object compound.As the base, the base mentioned above can be employed. Preferredexamples of the base include organic bases, particularly secondaryamines and tertiary amines. Among them, chain secondary amines,specifically dialkylamines such as di-C₁₋₈ alkylamines canadvantageously be employed. When such dialkylamine is used, the yield ofthe objective compound can remarkably be increased. Further, amongcyclic amines as above, use of such amines which are bulky, for examplepipecoline, may occasionally afford a high yield of the compound.

The amount of the base is, for example, about 0.5 to 10 gramequivalents, preferably about 1.0 to 5 gram equivalents and morepreferably about 1.2 to 3.5 gram equivalents relative to 1 mol of thecompound of the general formula (IV).

The reaction may be conducted in an inert solvent as mentioned above.Preferred examples of the solvent include hydrocarbons such as aromatichydrocarbons, aliphatic hydrocarbon and alicyclic hydrocarbons.

The amount of the compound of the general formula (IV) can be selectedfrom a suitable range with regard to the reaction rate and economicalfactors, and is generally about 0.3 to 1.5 gram equivalents andpreferably about 0.5 to 1.3 gram equivalents, and more preferably about0.8 to 1.2 gram equivalents relative to 1 mole of the compound of thegeneral formula (V).

According to this method, the amino group of the(R)-2-amino-1-phenylethanol derivative may attack the carbon atom on the2-position of the (S)-1-phenyl-2-substituted propane derivative of thegeneral formula (IV) from the opposite direction against the substituentY, and, thus, a substitution reaction with inversion can smoothlyproceed stereoselectively. Therefore, the corresponding(R,R)-1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol derivative ofthe general formula (VI) or a salt thereof with a by-produced acid HY,wherein Y has the same meaning as defined above, can be produced with ahigh reaction yield and optical yield.

The (R,R)-1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol derivativeand a salt thereof thus obtained can selectively react with theβ₃-receptor in vivo to decrease or reduce blood sugar significantly andto remarkably restrain or suppress obesity. The pharmacological activityin the (R,R)-isomer is extremely higher than those in the other opticalisomers. (R,R)-[disodium5-[2-[[2-(3-chlorophenyl)-2hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate]shows, for example, a higher activity than the corresponding(S,S)-enantiomer by a factor of 47 (see the above-mentioned U.S.Patent).

When the corresponding (R)-enantiomer is used instead of the(S)-1-phenyl-2-substituted propane derivative in the reaction, theobject compound (R,R)-1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanolderivative can hardly be produced. Further, use of the racemic1-phenyl-2-substituted propane derivative produces the objectivecompound only with a yield of 50% at most, and an isolating process forisolating and removing a by-produced optical isomer is required.

As described above, the (S)-1-phenyl-2-substituted propane derivative ofthe present invention is remarkably usable and effective intermediate toselectively obtain the(R,R)-1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol derivativeefficiently with a high yield, thus the (S)-enantiomer is remarkablymore usable than the corresponding (R)-enantiomer and the racemic form.

Further, the (S)-1-phenyl-2-substituted propane derivative of theformula (I) of the invention, differing from the(R)-1-methyl-2-phenylethylamine derivative, does not have anantihypnotic or arousal action, therefore is easy to handle or treat andsuited for a use in commercial production.

R¹, R² or the both of the compound of the general formula (VI) can beconverted from one substituent to another by a conventional manner. Assuch manner, the methods explained in R¹ and R² of the compound of thegeneral formula (I) may be referred to.

For example, (R,R)-1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanolderivative of the general formula (VI) where R¹ and R² are both methylgroups can easily be converted to the compound where R¹ and R²incorporatively form the group shown by the formula (IX) in accordancewith the above mentioned method. With regard to the method, thedisclosures and descriptions in the above mentioned U.S. Pat. No.5,061,727 and J. Med. Chem., 35, 3081 (1992) can be referred andincorporated with the present specification.

In the reaction, a compound having the group of the formula (IX) whereR^(a) and R^(b) are both optionally substituted alkoxycarbonyl groups,can be prepared by allowing a demethylating agent such as BBr₃ to reactwith the compound of the general formula (VI) where R¹ and R² are bothmethyl groups for demethylation, and allowing a dihalomalonic acid estershown by the formula (XI) such as diethyl dibromomalonate to react withthe demethylated compound in the presence of a base such as potassiumcarbonate. The resultant compound can be introduced to a compound havingthe group of the formula (IX) where R^(a) and R^(b) are both hydroxylgroups by using a reducing agent such as lithium borohydride. Whenallowing an alkyl halide of the formula (XII) to react with theresulting compound in the presence of a base such as sodium hydride, acompound having the group of the formula (IX) where R^(a) and R^(b) arerespectively an optionally substituted alkoxymethyl group can beprepared.

Further, hydrolysis of the compound having the group of the formula (IX)where R^(a) and R^(b) are respectively an optionally substitutedalkoxycarbonyl group, in accordance with a conventional hydrolyzingmethod such as alkali hydrolysis using an alkali such as an alkali metalhydroxide (e.g. sodium hydroxide) or the like can easily or readilyafford a compound having the group of the formula (IX) wherein R^(a) andR^(b) are, the same or different, a carboxyl group or a salt thereof.

The (R,R)-1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol derivativeof the general formula (VI) or a salt thereof produced in theabove-mentioned reaction can be recovered by a conventional isolationand purification technique. For instance, the(R,R)-1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol derivative or asalt thereof having a high optical purity can easily or readily beobtained by subjecting the reaction mixture, if necessary afteradjusting to alkaline, to the conventional purification procedure suchas extraction with an organic solvent, vacuum concentration, columnchromatography, distillation, crystallization and recrystallization.

The (R,R)-1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol derivativeor a salt thereof can advantageously be used, as intact or, wherenecessary, subjected to a suitable chemical modification, as amedicament such as an anti-obesity agent and an antidiabetic agent. Theprocesses for such chemical modification may be referred to thedescriptions and disclosures in, for example, the above-mentioned U.S.Pat. No. 5,061,727, J. Med. Chem., 35, 3081 (1992) and “Protectivegroups in Organic Synthesis” (T. W. Greene, A Wiley-IntersciencePublication, John Wiley & Sons (1981)).

The (R)-1-phenyl-2-substituted propane derivative shown by the generalformula (VII) and production thereof are illustrated hereinbelow.

As examples and preferred R¹ to R⁵ and X of the general formula (VII),there may be mentioned the substituents as mentioned above for thegeneral formula (I).

Among (R)-1-phenyl-2-substituted propane derivatives of the generalformula (VII), preferred examples include compounds where R¹ and R² are,the same or different, (i) a hydrogen atom, a C₁₋₄ alkyl group(specifically a methyl group) or (ii) R¹ and R² incorporatively form anoptionally substituted methylene group of the formula (IX) wherein R^(a)and R^(b) are respectively a carboxyl group or a salt thereof, or a C₂₋₅alkoxycarbonyl group; R³, R⁴, and R⁵ are independently a hydrogen atomor a C₁₋₄ alkyl group; and X is a hydroxyl group, a C₁₋₂alkylsulfonyloxy group, a C₆₋₁₅ arylsulfonyloxy group or a halogen atom.

Practical examples of the (R)-1-phenyl-2-substituted propane derivativeshown by the general formula (VII) can refer the examples of thecorresponding (S)-1-phenyl-2-substituted propane derivative of thegeneral formula (I) as mentioned above. Such examples include (1) an(R)-1-(3,4-dihydroxyphenyl)-2-substituted propane derivative, (2) an(R)-1-(3,4-di-C₁₋₄ aloxyphenyl)-2-substituted propane derivative, (3) an(R)-1-(2,2-di-C₁₋₄ alkyl-1,3-benzodioxol-5-yl)-2-substituted propanederivative, (4) an (R)-1-[2,2-bis(C₂₋₅alkoxycarbonyl)-1,3-benzodioxol-5-yl]-2-substituted propane derivativeand (5) an (R)-1-(2,2-dicarboxy-1,3-benzodioxol-5-yl)-2-substitutedpropane derivative.

As the (1) (R)-1-(3,4-dihydroxyphenyl)-2-substituted propane derivative,there may be mentioned, for instance,(R)-1-(3,4-dihydroxyphenyl)-2-propanol,(R)-[2-(3,4-dihydroxyphenyl)-1-methylethyl p-toluenesulfonate],(R)-[2-(3,4-dihydroxyphenyl)-1-methylethyl methanesulfonate],(R)-2-chloro-1-(3,4-dihydroxyphenyl)propane,(R)-2-bromo-1-(3,4-dihydroxyphenyl)propane and the like.

Examples of the (2) (R)-1-(3,4-di-C₁₋₄ alkoxyphenyl)-2-substitutedpropane derivative include (R)-1-(3,4-dimethoxyphenyl)-2-propanol,(R)-[2-(3,4-dimethoxyphenyl)-1-methylethyl p-toluenesulfonate],(R)-[2-(3,4-dimethoxyphenyl)-1-methylethyl methanesulfonate],(R)-2-chloro-1-(3,4-dimethoxyphenyl)propane,(R)-2-bromo-1-(3,4-dimethoxyphenyl)propane and so on.

The (3) (R)-1-(2,2-di-C₁₋₄ alkyl-1,3-benzodioxol-5-yl)-2-substitutedpropane derivative includes, for example,(R)-1-(2,2-dimethyl-1,3-benzodioxol-5-yl)-2-propanol,(R)-[1-methyl-2-(2,2-dimethyl-1,3-benzodioxol-5-yl)ethylp-toluenesulfonate],(R)-[1-methyl-2-(2,2-dimethyl-1,3-benzodioxol-5-yl)ethylmethanesulfonate],(R)-2-chloro-1-(2,2-dimethyl-1,3-benzodioxol-5-yl)propane,(R)-2-bromo-1-(2,2-dimethyl-1,3-benzodioxol-5-yl)propane, etc.

As examples of the (4) (R)-1-[2,2-bis(C₂₋₅alkoxycarbonyl)-1,3-benzodioxol-5-yl]-2-substituted propane derivative,there may be mentioned (R)-[dimethyl5-(2-hydroxypropyl)-1,3-benzodioxole-2,2-dicarboxylate], (R)-[diethyl5-(2-hydroxypropyl)-1,3-benzodioxole-2,2-dicarboxylate], (R)-[dimethyl5-[2-(p-toluenesulfonyloxy)propyl]-1,3-benzodioxole-2,2-dicarboxylate],(R)-[diethyl5-[2-(p-toluenesulfonyloxy)propyl]-1,3-benzodioxole-2,2-dicarboxylate],(R)-[dimethyl5-[2-(methanesulfonyloxy)propyl]-1,3-benzodioxole-2,2-dicarboxylate],(R)-[diethyl5-[2-(methanesulfonyloxy)propyl]-1,3-benzodioxole-2,2-dicarboxylate],(R)-[dimethyl 5-(2-chloropropyl)-1,3-benzodioxole-2,2-dicarboxylate],(R)-[diethyl 5-(2-chloropropyl)-1,3-benzodioxole-2,2-dicarboxylate],(R)-[dimethyl 5-(2-bromopropyl)-1,3-benzodioxole-2,2-dicarboxylate],(R)-[diethyl 5-(2-bromopropyl)-1,3-benzodioxole-2,2-dicarboxylate] andthe like.

Examples of the (5)(R)-1-(2,2-dicarboxy-1,3-benzodioxol-5-yl)-2-substituted propanederivative include (R)-[disodium5-[2-(hydroxypropyl)-1,3-benzodioxole-2,2-dicarboxylate], (R)-[disodium5-[2-(p-toluenesulfonyloxy)propyl]-1,3-benzodioxole-2,2-dicarboxylate],(R)-[disodium5-[2-(methanesulfonyloxy)propyl]-1,3-benzodioxole-2,2-dicarboxylate],(R)-[disodium 5-(2-chloropropyl)-1,3-benzodioxole-2,2-dicarboxylate],(R)-[disodium 5-(2-bromopropyl)-1,3-benzodioxole-2,2-dicarboxylate] andothers.

The (R)-1-phenyl-2-substituted propane derivative of the general formula(VII) can be prepared by a variety of methods, for example, thosementioned in the (S)-1-phenyl-2-substituted derivative of the generalformula (I) can be referred, and the object compound of the formula(VII) can advantageously be produced with the use of an action of amicroorganism or a preparation thereof.

For example, the (R)-1-phenyl-2-substituted propane derivative shown bythe general formula (VII) where X is a hydroxyl group, that is thecompound of the formula (VII′), can readily be obtained by permitting amicroorganism or a preparation thereof to act on the phenylacetonederivative of the general formula (II) to asymmetrically reduce andharvesting or recovering the product optically active(R)-1-phenyl-2-substituted propane derivative.

Any strain of microorganism that is capable of asymmetrically reducingthe phenylacetone derivative of the general formula (II) to produce theoptically active (R)-1-phenyl-2-substituted propanol derivative (VII′)can be used in the method.

Examples of such microorganism include a strain of microorganismsbelonging to the genus Corynebacterium, the genus Xanthomonas, the genusMicrococcus, the genus Botryoascus and the genus Candida.

(75) The strain of microorganism belonging to the genus Corynebacteriumincludes Corynebacterium variabilis JCM 2154, etc.

(76) The strain of microorganism belonging to the genus Xanthomonasincludes Xanthomonas sp. IFO 3085, etc.

(77) The strain of microorganism belonging to the genus Micrococcusincludes Micrococcus luteus AHU 1427, etc.

(78) The strain of microorganism belonging to the genus Botryoascusincludes Botryoascus synaedendrus IFO 1604, etc.

(79) The strain of microorganism belonging to the genus Candida includesCandida parapsilosis IFO 0585, etc.

For producing the optically active (R)-1-phenyl-2-substituted propanederivative of the formula′ (VII), any of wild strains, mutants andrecombinant strains which can be obtained by a genetic engineeringtechnique such as cell fusion or gene manipulation can preferably beemployed, as far as having the above mentioned ability or capability.

The strains of microorganisms each designated by IFO, JCM or AHU numberscan be available from the above-identified organizations.

The cultivation of the microorganism, asymmetric reduction and recoveryof the reaction product can be conducted by similar manners as in theproduction of the (S)-1-phenyl-2-substituted propane derivative of thegeneral formula (III).

In the (R)-1-phenyl-2-substituted propane derivative of the generalformula (VII), R¹ and R² can be converted from one substituent toanother by a conventional manner similarly in the compound (I).

The (R)-1-phenyl-2-substituted propane derivative of the formula (VII)may be converted to the (S)-1-phenyl-2-substituted propane derivative ofthe formula (I) by, for example, subjecting the (R)-enantiomer tonucleophilic substitution reaction accompanied with a steric inversion.Such reaction can be conducted with the use of a nucleophilic reagentfor introducing X or a group convertible to X to produce a stericallyinverted (S)-enantiomer.

The (R)-1-phenyl-2-substituted propane derivative where X is a hydroxylgroup, that is, the compound of the general formula (VII′) can easily beconverted to the (S)-1-phenyl-2-substituted propane derivative of thegeneral formula (I) wherein X is a hydroxyl group or a halogen atom,namely, the compound shown by the general formula (VIII) by selecting anreagent, a catalyst and reaction conditions from a suitable rangewherein the reaction is proceeded with steric inversion. For example,the reaction can be carried out in accordance with the following scheme:

In the general formula (VIII), X¹ represents a hydroxyl group or ahalogen atom. The halogen atom includes halogen atoms as mentionedabove.

The conversion of the compound of the general formula (VII′) to thecompound of the general formula (VIII) wherein X¹ is a hydroxyl groupcan be carried out by, for example, the following method according toMitsunobu reaction.

The (S)-1-phenyl-2-substituted propane derivative of the general formula(VIII) wherein X¹ is a hydroxyl group can be obtained by allowing anorganic acid to react with the compound of the general formula (VII′) inthe presence of triarylphosphine (e.g. triphenylphosphine, etc.) and anazodicarboxylic acid ester such as ethyl azodicarbonate to form thesterically inverted corresponding organic acid ester, and hydrolyzingthe resulting ester. The organic acid includes, for example, formicacid, acetic acid, trichloroacetic acid, trifluoroacetic acid, benzoicacid and the like. The formation of the organic acid ester may beconducted, for example, at a temperature of about −60° C. to 60° C. Thereaction may be carried out in an inert solvent such as an aromatichydrocarbon (for example, benzene, toluene and so on) and an ether (e.g.tetrahydrofuran, etc.). The proportions of triarylphosphine, organicacid and azodicarboxylic acid ester based on 1 mole of the compound ofthe general formula (VII′) are respectively about 0.7 to 2.0 moles. Thehydrolysis of the organic acid ester can be conducted by a conventionalmanner such as acid-hydrolysis or alkali-hydrolysis.

Such method utilizing Mitsunobu reaction wherein an optically activealcohol is sterically inverted to the corresponding optically activealcohol may refer to methods or those analogous thereto described, forexample, in Synthesis, 1 (1981); Tetrahedron Lett., 1619 (1973); andBull. Chem. Soc. Jpn., 44, 3427 (1971), and these descriptions can beincorporated to the present specification.

For the conversion of the optically active alcohol to the correspondingenantiomer, following methods can also be applied:

(a) the method comprising esterifying an optically active alcohol to acarboxylic acid ester such as trichloroactic acid ester, and hydrolyzingthe resultant carbosylic acid ester, in a water-ether solvent such as75% H₂O-dioxane, can also be applied (see Chem. Lett., 1976, 893), and

(b) the method which comprises (a) converting an optically activealcohol to a sulfonic acid ester such as p-toluenesulfonic acid ester,(b) allowing an organic acid salt such as tetraethylammonium acetate andsodium acetate (-acetic acid) to react with the resulting sulfonic acidester to sterically invert to the corresponding organic acid ester, and(c) hydrolyzing the resultant organic acid ester (J. Am. Chem. Soc., 87,3682, (1965); and J. Chem. Soc., 1954, 965).

The (S)-1-phenyl-2-substituted propane derivative of the general formula(VIII) wherein X¹ is a halogen atom can be prepared from the compound ofthe formula (VII′) by choosing a reagent, a catalyst, a solvent, andother reaction conditions from an adequate range as far as the reactionmay be conducted with sterically inverting.

The conversion of the compound of the general formula (VII′) to thecompound of the general formula (VIII) wherein X¹ is a halogen atom canbe carried out, for example, by the following procedure (J. Chem. Soc.,1709 (1953); and J. Chem. Soc., 3795 (1954)).

The reaction can be carried out by allowing a halogenating agent such asphosphorus pentachloride, phosphorus pentabromide, thionyl chloride andthionyl bromide to react with the compound of the general formula (VII′)in the presence of a base such as the inorganic base (e.g. calciumcarbonate) and the organic base as mentioned above to invert thecompound sterically. The halogenation may be carried out, for instance,at about −20° C. to 150° C. The reaction may be conducted in an inertsolvent such as an aromatic hydrocarbon (for instance, benzene, tolueneand the like) and a halogenated hydrocarbon (e.g. methylene chloride,chloroform and so on). Where thionyl chloride or thionyl bromide isemployed, the reaction may frequently be carried out in the presence ofa base as exemplified above, or an organic base may frequently be usedas the solvent to improve the inversion rate. Examples of such organicbase include amines such as triethylamine, N,N-dimethylaniline andN-methylpiperidine; and nitrogen-containing heterocyclic compounds suchas pyridine and picoline.

The proportion of the halogenating agent relative to 1 gram equivalentof the (R)-1-phenyl-2-propanol derivative of the general formula (VII′),is, for example, about 0.9 gram equivalent or more, and preferably about0.9 to 1.5 gram equivalents. A reaction accelerator such as sodiumchloride, sodium bromide and N,N-dimethylformamide may be added to thereaction system in order to proceed the reaction steadily or smoothly.

For the conversion of the (R)-1-phenyl-2-substituted propane derivativeof the general formula (VII′) to the (S)-1-phenyl-2-substituted propanederivative of the general formula (I) where X is a halogen atom, thefollowing descriptions in literatures can also be referred andincorporated into the present specification:

(1) the method allowing a methanesulfonyl halide (e.g. methanesulfonylchloride) to react with an optically active alcohol in the presence of abase and lithium halide such as lithium chloride (J. Org. Chem., 56,2769 (1991)),

(2) the method comprising allowing a p-toluenesulfonyl halide (e.g.p-toluenesulfonyl chloride) to react with an optically active alcohol inthe presence of a base to produce a p-toluenesulfonic acid ester andallowing the resultant ester to react with a tetraalkylammonium halidesuch as tetraalkylammonium chloride (Tetrahedron Lett., 3425 (1990)),

(3) the method allowing an N,N-dialkyl-1,2,2-trihalovinylamine (e.g.N,N-diethyl-1,2,2-trichlorovinylamine) to react with an optically activealcohol (J. Am. Chem. Soc., 82, 909 (1960)),

(4) the method where a tetraalkyl-α-halogenoenamine (for instance,tetramethyl-α-chloroenamine) to react with an optically active alcohol(Tetrahedron Lett., 30, 3077 (1989)),

(5) the method allowing gaseous hydrochloric acid to react with amixture of an optically active alcohol and nitrile to convert ahalogenated compound via an imidate (J. Am. Chem. Soc., 77, 2341 (1955);Ber. Deutsch Chem. Ges., 92, 370 (1959); and Tetrahedron Lett., 2517(1970)),

(6) the method where a carbon tetrahalide such as carbon tetrachlorideand carbon tetrabromide is allowed to react with an optically activealcohol in the presence of triphenylphosphine (J. Org. Chem., 56, 3009(1991); and Chem. Ind (London), 1017 (1969)),

(7) the method allowing an azodicarboxylic acid ester such as ethylazodicarbonate, and a methyl halide such as methyl bromide to react withan optically active alcohol in the presence of triphenylphosphine(Tetrahedron, 39, 2591 (1983)),

(8) the method allowing a zinc halide (e.g. zinc chloride), anazodicarboxylic acid ester (for instance, ethyl azodicarbonate) andtriphenylphosphine to react with an optionally active alcohol (J. Org.Chem., 49, 3027 (1984); Tetrahedron Lett., 28, 4199 (1987); and Herb.Chem. Acta, 32, 184 (1949)),

(9) the method which comprises allowing a 2-dialkylaminoN,N′-diphenyl-1,3,2-diazaphosphorane such as 2-dimethylaminoN,N′-diphenyl-1,3,2-diazaphosphorane to react with an optically activealcohol to produce a corresponding 2-alkoxyN,N′-diphenyl-1,3,2-diazaphosphorane and allowing a halogenating agent(e.g. sulfuryl chloride, bromine, methyl iodide, etc.) to react with theresulting compound (Tetrahedron Lett., 23, 4411 (1982)), and

(10) the method where 3-alkyl-2-fluorobenzothiazolium tetrafluoroboratesuch as 3-ethyl-2-fluorobenzothiazolium tetrafluoroborate to react withan optically active alcohol in the presence of a metal halide such assodium chloride, sodium bromide, sodium iodide, lithium chloride,lithium bromide and lithium iodide (Chem. Lett., 619 (1976)).

The obtained (S)-1-phenyl-2-substituted propane derivative of thegeneral formula (VIII) is an specifically important intermediate forproduction of the(R,R)-1-phenyl-2-[(2-phenyl-1-methylethyl)amino]ethanol derivative.Accordingly, the (R)-1-phenyl-2-substituted propane derivative of thegeneral formula (VII) of the present invention is remarkably usable asan intermediate material for the (S)-1-phenyl-2-substituted propanederivative.

The methods for conversion of the (R)-1-phenyl-2-substituted propanederivative of the general formula (VII) to the(S)-1-phenyl-2-substituted propane derivative of the general formula (I)can also be applied to the conversion of the corresponding(S)-enantiomer to the (R)-enantiomer.

The following examples are intended to illustrate the invention infurther detail and should by no means be construed as delimiting thescope of the invention.

EXAMPLES

The quantitative determination and optical purity determination of1-(3,4-dimethoxyphenyl)-2-propanol in the reaction mixture were carriedout by subjecting the reaction mixture to high performance liquidchromatography using an optical resolution column (column: Chiralcel OF(trade name), Daicel Chemical Industries, Ltd.; solvent:n-hexane/2-propanol=90/10; flow rate: 1 ml/min.; temperature: 40° C.;wavelength: 220 nm).

Examples 1 to 139 Production of (S)-1-(3,4-dimethoxyphenyl)-2-propanol

YM Medium (0.3% by weight of yeast extract, 0.3% by weight of maltextract, 0.5% by weight of peptone, 2% by weight of glucose, pH 6.0) wasused for strains of microorganism belonging to yeasts, and PM medium (2%by weight of glucose, 0.3% by weight of peptone, 0.5% by weight of yeastextract, 0.3% by weight of meat extract, 0.2% by weight of ammoniumsulfate, 0.1% by weight of potassium dihydrogenphosphate, 0.05% byweight of magnesium sulfate, pH 7.0) was used for strains ofmicroorganism belonging to bacteria.

A test tube of diameter of 21 mm was charged with 5 ml of the abovementioned medium respectively. After sterilization, the tube wasinoculated with one of the following microbial strains. The inoculatedtube was incubated under shaking at 30° C. for 24 hours.

Example 1: Sphingobacterium sp. IFO 13310

Example 2: Aeromonas hydrophila subsp. proteolytiga IFO 13287

Example 3: Agrobacterium radiobacter IFO 12664

Example 4: Aureobacterium testaceum IFO 12675

Example 5: Bacillus cereus AHU 1355

Example 6: Cellulomonas flavigena IFO 3754

Example 7: Chromobacterium iodinum IFO 3558

Example 8: Corynebacterium aquaticum IFO 12154

Example 9: Gluconobacter oxydans IFO 3255

Example 10: Jensenia canicruria IFO 13914

Example 11: Comamonas acidovorans IFO 13582

Example 12: Pseudomonas fluorescens IFO 3081

Example 13: Pseudomonas putida IFO 3738

Example 14: Alternaria japonica IFO 5244

Example 15: Amanita citrina IFO 8261

Example 16: Aspergillus awamori nakazawa IFO 4033

Example 17: Aspergillus ficuum IFO 4018

Example 18: Aspergillus niger AHU 7105

Example 19: Aspergillus niger IFO 5374

Example 20: Cochliobolus miyabeanus IFO 6631

Example 21: Corynespora cassiicola IFO 6724

Example 22: Dactylium dendroides ATCC 46032

Example 23: Drechslera avenae IFO 6636

Example 24: Echinopodospora jamaicensis IFO 9819

Example 25: Gelasinospora cerealis IFO 6759

Example 26: Gonatobotryum apiculatum IFO 9098

Example 27: Helminthosporium sigmoideum var. irregulare IFO 5273

Example 28: Mortierella isabeilina IFO 6336

Example 29: Paecilomyces variotii IFO 4855

Example 30: Phialophora pedrosoi IFO 6071

Example 31: Phytophthora capsici IFO 8386

Example 32: Podospora carbonaria IFO 30294

Example 33: Rhizomucor pusillus IFO 4578

Example 34: Septoria glycines IFO 5294

Example 35: Sporormielia isomera IFO 8538

Example 36: Stemphylium sarciniforme IFO 7243

Example 37: Talaromyces flavus var. flavus IFO

Example 38: Torula jeanselmei IFO 6857

Example 39: Ustilago cynodontis IFO 7530

Example 40: Westerdykella multispora IFO 5813

Example 41: Ambrosiozyma cicatricosa IFO 1846

Example 42: Ambrosiozyma monospora IFO 1965

Example 43: Dekkera custersianus IFO 1585

Example 44: Candida aaseri IFO 10104

Example 45: Candida atomspherica IFO 1969

Example 46: Candida beechii IFO 10229

Example 47: Candida diversa IFO 1091

Example 48: Candida ergatensis IFO 10233

Example 49: Candida fluviatilis IFO 10234

Example 50: Candida fusiformate IFO 10225

Example 51: Candida glabrata IFO 0622

Example 52: Candida gropengiesseri IFO 0659

Example 53: Candida halonitratophila IFO 1595

Example 54: Candida inconspicua IFO 0621

Example 55: Candida kefyr DSM 70073

Example 56: Candida krusei DSM 70075

Example 57: Candida lambica DSM 70090

Example 58: Candida mogii IFO 0436

Example 59: Candida maltosa IFO 1978

Example 60: Candida melibiosica IFO 10238

Example 61: Candida membranaefaciens IFO 1246

Example 62: Candida oleophila JCM 2444

Example 63: Candida parapsilosis IFO 1022

Example 64: Candida pintolopeslii var. pintolopeslii IFO 0729

Example 65: Candida pseudointermedia IFO 1693

Example 66: Candida catenulata DSM 70136

Example 67: Candida rugosa IFO 0591

Example 68: Candida saitoana IFO 0768

Example 69: Candida sake IFO 1149

Example 70: Candida natalensis IFO 1981

Example 71: Candida salmanticensis IFO 10242

Example 72: Candida santamariae IFO 1982

Example 73: Candida schatavii IFO 10258

Example 74: Candida shehatae IFO 1983

Example 75: Candida silvanorum IFO 10419

Example 76: Candida sorbophila IFO 1583

Example 77: Candida tenuis IFO 10315

Example 78: Candida utilis IFO 0396

Example 79: Candida utilis IFO 0988

Example 80: Candida albicans IFO 0759

Example 81: Clavispora lusitaniae IFO 1019

Example 82: Cryptococcus humicolus IFO 0760

Example 83: Cryptococcus neoformans IAM 4788

Example 84: Debaryomyces varijiae DSM 70252

Example 85: Galactomyces reessii IFO 1112

Example 86: Filobasidium capsuligenum IFO 1119

Example 87: Geotrichum candidum IFO 4598

Example 88: Geotrichum fermentans JCM 2467

Example 89: Geotrichum fragrans JCM 2450

Example 90: Hansenula polymorpha ATCC 26012

Example 91: Hansenula capsulata DSM 70269

Example 92: Hansenula glucozyrna DSM 70271

Example 93: Hansenula wickerhamii DSM 70280

Example 94: Issatchenkia scutulata var. scutulata IFO 10070

Example 95: Kloeckera africana IFO 0869

Example 96: Kluyveromiyces lactis IFO 0433

Example 97: Kluyveromyces marxianus DSM 70800

Example 98: Kluyveromyces polysporus DSM 70294

Example 99: Leucosporidium scottii IFO 1924

Example 100: Lodderomyces elongisporus IFO 1676

Example 101: Metschnikowia bicuspidata IFO 1408

Example 102: Metschnikowia pulcherrima DSM 70336

Example 103: Metschnikowia reukaufii DSM 70880

Example 104: Myxozyyma lipomycoides IFO 10350

Example 105: Oosporidiumn margaritiferum IFO 1208

Example 106: Pachysolen tannophilus IFO 1007

Example 107: Pichia cellobiosa DSM 2147

Example 108: Pichia farinosa IFO 1163

Example 109: Pichia lindnerii DSM 70718

Example 110: Pichia ohmeri DSM 70815

Example 111: Pichia thermotolerans IFO 10025

Example 112: Pichia pastoris DSM 70382

Example 113: Pichia trehalophila DSM 70391

Example 114: Pichia carsonlii DSM 70392

Example 115: Pichia subpelliculosa IFO 0808

Example 116: Malassezia furfur IFO 0656

Example 117: Rhodosporidium diobovatum IFO 1830

Example 118: Rhodosporidium toruloides IFO 1638

Example 119: Kondoa malvinella IFO 1936

Example 120: Rhodotorula glutinis AHU 3454

Example 121: Rhodotorula rubra IFO 0383

Example 122: Saccharomyces rouxii IAM 0487

Example 123: Octosporomyces octosporus IFO 0353

Example 124: Sporidiobolus johnsonii IFO 6903

Example 125: Sporidiobolus pararoseus IFO 1104

Example 126: Sporidiobolus salmonicolor IFO 1845

Example 127: Sporobolomyces pararoseus IFO 1036

Example 128: Sporopachydermia lactativora IFO 1867

Example 129: Sterigmatomyces elviae DSM 70852

Example 130: Torulaspora delbrueckii IFO 0381

Example 131: Torulopsis nemodendra DSM 70647

Example 132: Trigonopsis variabilis IFO 0755

Example 133: Wickerhamia fluorescens DSM 70715

Example 134: Wickerhamiella domercquii IFO 1857

Example 135: Wingea robertsii IFO 1277

Example 136: Zygoascus hellenicus IFO 1575

Example 137: Zygosaccharomyces bailii IFO 0468

Example 138: Zygosaccharomyces bisporus DSM 70415

Example 139: Zygozyma oligophaga IFO 10360

The cells were isolated by centrifuging and suspended in 1 ml of 0.1Mphosphate buffer (pH 7.0) containing 0.5% by weight of3,4-dimethoxyphenylacetone and 5% by weight of glucose. A test tube of21 mm diameter was charged with the suspension and reaction wasconducted on a reciprocating shaker at 30° C. for 48 hours.

After completion of the reaction, the reaction suspension was added witha small amount of sodium chloride and extracted with 5 ml of n-hexane.The n-hexane extract was subjected to determination and the opticalpurity and the yield of the product 1-(3,4-dimethoxyphenyl)-2-propanolwere determined. The results are set forth in Tables 1 to 7.

TABLE 1 (S)-1-(3, 4-dimethoxy- phenyl)-2-propanol Example Yield Opticalpurity No. (%) (% e.e.) 1 39.5 29.1 2 29.2 94.6 3 10.9 91.8 4 42.0 94.35 18.8 92.7 6 16.2 77.2 7 11.7 23.0 8 43.0 47.9 9 20.3 98.6 10 22.4 92.311 10.3 90.2 12 14.1 77.0 13 10.0 94.5 14 10.8 80.9 15 12.4 85.6 16 13.879.8 17 10.0 98.6 18 15.0 83.3 19 15.2 80.4 20 15.6 67.3

TABLE 2 (S)-1-(3, 4-dimethoxy- phenyl)-2-propanol Example Yield Opticalpurity No. (%) (% e.e.) 21 11.2 88.9 22 13.8 92.4 23 11.0 95.8 24 21.098.0 25 26.0 94.4 26 13.8 67.0 27 14.8 98.3 28 17.2 96.2 29 32.0 93.9 3011.4 84.9 31 28.4 96.7 32 10.6 82.4 33 15.0 92.0 34 12.8 91.0 35 12.864.2 36 13.2 69.7 37 15.0 93.9 38 26.4 25.9 39 11.8 94.7 40 18.2 72.2

TABLE 3 (S)-1-(3, 4-dimethoxy- phenyl)-2-propanol Example Yield Opticalpurity No. (%) (% e.e.) 41 28.4 95.8 42 22.2 97.0 43 12.2 95.6 44 43.497.7 45 24.6 93.8 46 19.0 92.0 47 14.9 66.2 48 37.5 38.3 49 34.3 69.4 5015.4 79.0 51 18.5 93.3 52 21.4 66.7 53 15.8 76.9 54 10.6 77.5 55 35.299.2 56 17.2 66.2 57 47.1 98.6 58 19.2 80.2 59 21.9 19.1 60 15.7 96.2

TABLE 4 (S)-1-(3, 4-dimethoxy- phenyl)-2-propanol Example Yield Opticalpurity No. (%) (% e.e.) 61 40.8 81.6 62 25.2 76.4 63 22.4 85.0 64 10.784.2 65 10.7 57.0 66 10.3 89.3 67 21.6 89.3 68 21.5 98.2 69 69.1 96.9 7012.9 20.6 71 10.5 79.5 72 38.6 84.9 73 23.6 83.0 74 18.4 83.0 75 37.792.3 76 10.4 83.6 77 10.1 65.3 78 26.3 96.9 79 42.9 97.6 80 34.2 87.0

TABLE 5 (S)-1-(3, 4-dimethoxy- phenyl)-2-propanol Example Yield Opticalpurity No. (%) (% e.e.) 81 69.5 94.2 82 16.7 77.8 83 13.8 97.2 84 25.598.3 85 24.1 99.2 86 29.8 99.1 87 12.3 99.4 88 18.0 95.0 89 17.5 98.2 9066.1 97.3 91 34.0 99.0 92 44.7 86.6 93 25.8 76.5 94 10.2 75.5 95 14.853.0 96 27.9 96.4 97 40.9 93.0 98 22.1 92.2 99 35.0 95.9 100 33.8 62.1

TABLE 6 (S)-1-(3,4-dimethoxy- phenyl)-2-propanol Example Yield Opticalpurity No. (%) (% e.e.) 101 39.6 79.4 102 25.6 90.9 103 13.1 78.6 10438.4 99.0 105 14.8 52.9 106 24.6 96.3 107 15.4 78.6 108 34.9 92.8 10971.3 97.9 110 17.0 76.9 111 16.9 97.4 112 71.3 97.9 113 28.2 97.8 11419.3 90.1 115 13.3 98.5 116 13.9 78.2 117 29.9 96.4 118 86.3 98.4 11923.7 77.0 120 10.4 96.8

TABLE 7 (S)-1-(3, 4-dimethoxy- phenyl)-2-propanol Example Yield Opticalpurity No. (%) (% e.e.) 121 24.0 73.9 122 33.0 97.7 123 58.8 69.2 12464.4 97.4 125 12.6 94.8 126 18.3 94.3 127 19.9 95.2 128 38.4 99.0 12926.7 78.0 130 57.1 98.3 131 10.0 85.3 132 11.3 85.9 133 27.9 100 13416.4 92.3 135 10.4 95.2 136 34.2 94.8 137 11.5 93.9 138 23.4 93.2 13932.6 96.3

Example 140 Production of (S)-1-(3,4-dimethoxyphenyl)-2-propanol

A 2.6-liter mini jar fermenter was charged with 1.5 liter of YM media ofthe same composition as mentioned in Examples 1 to 139. Aftersterilization with the use of an autoclave, the fermenter was inoculatedwith Torulaspora delbrueckii IFO 0381, and the inoculated fermenter wasincubated at 30° C., under aeration at 1 vvm, with stirring at 400 rpmfor 24 hours. After completion of incubation, the cells wereconcentrated by centrifuging.

A 2.6-liter mini far fermenter was charged with 1 liter of 0.1Mphosphate buffer (pH 7.0) and the obtained cells were suspended therein.To the suspension was added 5 g of 3,4-dimethoxyphenylacetone and 50 gof glucose, and the reaction was carried out at 30° C., under aerationat 1 vvm, with stirring at 400 rpm for 48 hours.

After completion of the reaction, the cells were removed off bycentrifuging, and the obtained supernatant was added with 400 g ofsodium chloride, and extracted with 1 liter of ethyl acetate threetimes. The ethyl acetate extract was dried over anhydrous sodiumsulfate, and the solvent was removed under reduced pressure to give 3.1g of an oily substance. The oily substance was purified with the use ofsilica gel chromatography (eluent: n-hexane/ethyl acetate=7/3) to give2.7 g of crystalline (S)-1-(3,4-dimethoxyphenyl)-2-propanol (m.p.: 51°C.). The specific rotation of the compound was [α]_(D) ²⁰ +28.3°(c=1.06, chloroform). As a result of analyzing the compound by highperformance liquid chromatography using an optical resolution column(column: Chiralcel OF (trade name), Daicel Chemical Industries, Ltd.),the optical purity thereof was 100% e.e.

¹H-NMR (270 MHz, CDCl₃) δ: 1.24 (d, 3H), 1.72 (br, s, 1H), 2.66 (m, 2H),3.86 (d, 6H), 3.99 (m, 1H), 6.76 (m, 3H).

IR (cm⁻¹): 3400, 2880, 1515, 1460, 1260, 1240, 800.

The absolute configuration of the obtained1-(3,4-dimethoxyphenyl)-2-propanol was determined by the followingmanner.

The 1-(3,4-dimethoxyphenyl)-2-propanol obtained above was subjected tosulfonylation by p-toluenesulfonyl chloride and reacted with benzylamineto give N-benzyl-3,4-dimethoxyamphetamine. The resultant compound wasconverted into 3,4-dimethoxyamphetamine by hydrogenation decompositionunder hydrogen atmosphere with 5% Pd-C.

As a result of the determination of the obtained3,4-dimethoxyamphetamine, the specific rotation thereof was [α]_(D) ²⁵−26.5° (c=4.58, chloroform).

To an ethanol solution of the 3,4-dimethoxyamphetamine was added anequivalent amount of (half time as much mole of) concentrated sulfuricacid to yield 3,4-dimethoxyamphetamine.1/2H₂SO₄ as crystals. Thespecific rotation of the sulfuric acid salt was [α]_(D) ²⁵ −19.03°(c=2.27, H₂O). The obtained 3,4-dimethoxyamphetamine was determined asan (R)-form since the values in a literature (J. Org. Chem., 22, 33(1957)) are as follows.

(R)-3,4-dimethoxyamphetamine:

[α]_(D)−30.9° (c=4.13, chloroform)

(R)-3,4-dimethoxyamphetamine.1/2H₂SO₄:

[α]_(D)−21.4° (c=2.0, H₂O)

Since the reaction where 3,4-dimethoxyamphetamine is produced from1-(3,4-dimethoxyphenyl)-2-propanol is accompanied by inversion, the1-(3,4-dimethoxyphenyl)-2-propanol obtained above was proved to be an(S)-enantiomer.

Example 141 Production of (S)-[2-(3,4-dimethoxyphenyl)-1-methylethylp-toluenesulfonate

To a solution of 404 mg of (S)-1-(3,4-dimethoxyphenyl)-2-propanol in 2ml of pyridine was added 472 mg of p-toluenesulfonyl chloride undernitrogen atmosphere on an ice bath. The mixture was stirred at 20° C.for 17 hours. Granules of ice were added to the mixture to cease thereaction, and the reaction mixture was stirred for further 30 minutes.The reaction mixture was acidified by adding 2N hydrochloric acid andwas extracted twice with 20 ml of chloroform. The organic extract waswashed with a saturated aqueous solution of sodium chloride, dried overanhydrous magnesium sulfate, distilled off the solvent to give 716 mg of(S)-[2-(3,4-dimethoxyphenyl)-1-methylethyl p-toluenesulfonate] as whitecrystals (yield: 98%). Analysis of the compound by high performanceliquid chromatography using an optical resolution column (columnChiralcel OF (trade name), Daicel Chemical Industries, Ltd.) revealedthat the optical purity thereof was 100% e.e.

m.p.: 62.4 to 62.8° C.

[α]_(D) ²⁵+20.6° (c=1.0, chloroform)

IR (KBr) (cm⁻¹): 3044, 2995, 2937, 1594, 1517, 1357, 1346, 1262, 1243,1187, 1178, 1169, 1157, 1142, 1029, 913, 889, 854, 806, 766, 666, 578,558.

¹H-NMR (500 MHz, CDCl₃) δ: 1.34 (d, 3H), 2.41 (s, 3H), 2.73 (dd, 1H),2.83 (dd, 1H), 3.76 (s, 3H), 3.86 (s, 3H), 4.70 (m, 1H), 6.47 (d, 1H),6.59 (m, 1H), 6.69 (d, 1H), 7.24 (d, 2H), 7.57 (d, 2H).

¹³C-NMR (125 MHz, CDCl₃) δ: 20.74, 21.49, 42.48, 55.54, 55.76, 80.88,110.90, 112.21, 121.44, 127.48, 128.80, 129.41, 133.48, 144.19, 147.81,148.61.

Example 142 Production of(R,R)-1-(3-chlorophenyl)-2-[2-(3,4-dimethoxyphenyl)-1methylethyllaminolethanol

(R)-2-Amino-1-(3-chlorophenyl)ethanol (806 mg) was added to(S)-[2-(3,4-dimethoxyphenyl)-1-methylethyl p-toluenesulfonate] (700 mg)under nitrogen atmosphere, and the mixture was stirred at 60° C. for 31hours. The reaction mixture was adjusted to alkaline by adding a 10%aqueous solution of sodium hydroxide, and extracted twice with 20 ml ofchloroform. The organic extract was dried over anhydrous sodium sulfate,subjected to distilling off the solvent and to purifying with silica gelchromatography (eluent: chloroform/methanol) to give 550 mg of(R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanolas white crystals (yield: 79%). The NMR spectrum data are shown asfollows.

¹H-NMR (500 MHz, CDCl₃) δ: 1.09 (d, 3H), 2.08 (brs, 2H), 2.61-2.69 (m,3H), 2.87-2.92 (m, 2H), 3.86 (s, 3H), 3.87 (s, 3H), 4.55 (dd, 1H), 6.68(s, 1H), 6.70 (d, 1H), 6.80 (d, 1H), 7.18-7.26 (m, 3H), 7.35 (s, 1H).

¹³C-NMR (125 MHz, CDCl₃) δ: 20.37, 43.39, 54.09, 54.26, 55.87, 55.89,71.11, 111.21, 112.36, 121.19, 123.89, 125.94, 127.55, 129.61, 131.56,134.32, 144.66, 147.57, 148.87.

The optical purity of the compound was determined by converting thecompound into a corresponding cyclic urethane derivative. That is, thecompound was converted into(R,R)-5-(3-chlorophenyl)-3-[2-(3,4-dimethoxyphenyl)-1-methylethyl]-2-oxazolidinoneby allowing carbonyldiimidazole and N-methylmorpholine to react with thecompound in tetrahydrofuran at room temperature for 2 hours, thenheating the mixture under reflux for 3 hours. Analyzing the compound byhigh performance liquid chromatography using an optical resolutioncolumn (column: Chiralcel AS (trade name), Daicel Chemical Industries,Ltd.), the optical purity of the compound was 90% e.e. The NMR spectrumdata of the obtained cyclic urethane derivative are set forthhereinbelow.

¹H-NMR (500 MHz, CDCl₃) δ: 1.26 (d, 3H), 2.67 (dd, 1H), 2.81 (dd, 1H),3.24 (dd, 1H), 3.81 (s, 3H), 3.83 (dd, 1H), 3.86 (s, 3H), 4.33 (ddq,1H), 5.35 (dd, 1H), 6.63 (d, 1H), 6.70 (s, 1H), 6.73 (d, 1H), 6.91 (d,1H), 7.12 (s, 1H), 7.22 (dd, 1H), 7.28 (d, 1H).

¹³C-NMR (125 MHz, CDCl₃) δ: 17.72, 39.71, 47.69, 49.55, 55.75, 55.79,73.38, 111.03, 111.75, 120.76, 123.44, 125.56, 128.73, 129.76, 130.07,134.62, 141.14, 147.71, 148.90, 156.90.

Examples 143 to 147 Production of (R)-1-(3,4-dimethoxyphenyl)-2-propanol

The cultivating procedures and reaction procedures were conducted in thesame manner as in Examples 1 to 139 except for using the followingstrains of microorganisms. The results are shown in Table 8.

Example 143: Corynebacterium variabilis JCM 2154

Example 144: Xanthomonas sp. IFO 3085

Example 145: Micrococcus luteus AHU 1427

Example 146: Botryoascus synaedendrus IFO 1604

Example 147: Candida parapsilosis IFO 0585

TABLE 8 (R)-1-(3, 4-dimethoxy- phenyl)-2-propanol Example Yield Opticalpurity No. (%) (% e.e.) 143 12.6 74.9 144 18.6 83.9 145 19.3 53.2 14620.6 34.5 147 31.1 10.6

Example 148 Production of (S)-1-(3,4-dimethoxyphenyl)-2-propanol

(R)-1-(3,4-Dimethoxyphenyl)-2-propanol (0.9 g) was obtained as crystalsby cultivation, reaction and purification in the similar manners as inExample 140 except that PM medium was employed instead of YM media andthat Xanthomonas sp. IFO 3085 was used instead of Torulasporadelbrueckii IFO 0381. The crystals gave the same signals in ¹H-NMRanalysis as in the (S)-1-(3,4-dimethoxyphenyl)-2-propanol obtained inExample 140. Further the specific rotation of the crystals was “−”,therefore, the crystals were proved to be(R)-1-(3,4dimethoxyphenyl)-2-propanol. As a result of nation by highperformance liquid chromatography with the use of a optical resolutioncolumn, the optical purity of the compound was 85.5% e.e.

Thus obtained (R)-1-(3,4-dimethoxyphenyl)-2-propanol (744 mg, 3.80mmol.), triphenylphosphine (1196 mg) and formic acid (210 mg) weredissolved in 60 ml of tetrahyd-ofuran, and to the resultant solution,was added a solution of 794 mg of diethyl azodicarbonate in 10 ml oftetrahvdrofuran. The mixture was stirred at room temperature for 15hours, and reaction mixture was concentrated under reduced pressure. Theresulting residue was subjected to purification by silica gelchromatography (eluent: n-hexane/ethyl acetate=7/3) to give 595 mg offormic acid ester of (S)-1-(3,4-dimethoxyphenyl)-2-propanol. The esterwas subjected to alkali-hydrolysis according to a known method andextracted with ethyl acetate, and the solvent was distilled off. Theresidue was purified by silica gel chromatography (eluent:n-hexane/ethyl acetate=7/3) to give 450 mg of(S)-1-(3,4-dimethoxyphenyl)-2-propanol as crystals. The optical purityof the compound was 99% e.e. by analyzing by high performance liquidchromatography with the use of an optical resolution column.

Example 149 Production of(R,R)-1-(3-chlorophenyl)-2-[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanol

A mixture of 57.0 g (0.163 mol) of(S)-[2-(3,4-dimethoxyphenyl)-1-methylethyl p-toluenesulfonate], 33.7 g(0.196 mol) of (R)-2-amino-1-(3-chlorophenyl)ethanol, 33.7 g (0.244 mol)of anhydrous potassium carbonate and 133 ml of toluene was stirred at90° C. for 48 hours under nitrogen atmosphere. The reaction mixture wasadjusted to alkaline by adding a 10% aqueous solution of sodiumhydroxide and extracted twice with 500 ml of toluene. The tolueneextract was dried over anhydrous sodium sulfate, and subjected todistillation of the solvent and to purification with silica gelchromatography to give 34.8 g of1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanolas white crystals (yield: 61%). As a result of isolating and analyzingthe isomers with high performance liquid chromatography using an opticalresolution column (column: Chiralpack AD (trade name), Daicel ChemicalIndustries, Ltd.), the optical purity of the title compound was 86.8%[(R,R)/(R,S)=86.8/13.2].

Example 150 Production of(R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanol

Under nitrogen atmosphere, a mixture of 4.20 g (0.0120 mol) of(S)-[2-(3,4-dimethoxyphenyl)-1-methylethyl p-toluenesulfonate], 2.47 g(0.0144 mol) of (R)-2-amino-1-(3-chlorophenyl)ethanol and 1.82 g (0.0180mol) of diisopropylamine was stirred at 60° C. for 48 hours. Thereaction mixture was adjusted to alkaline by adding a 10% aqueoussolution of sodium hydroxide and extracted twice with 500 ml of toluene.The toluene extract was dried over anhydrous sodium sulfate, andsubjected to distillation of the solvent and to purification with silicagel chromatography to give 3.23 g of1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-1-methylethyl]amino]ethanolas white crystals (yield: 77%). As a result of isolation and analysis ofthe isomers by high performance liquid chromatography using an opticalresolution column (column: Chiralpack AD (trade name), Daicel ChemicalIndustries, Ltd.), the optical purity of the objective compound was92.8% [(R,R) (R,S)=92.8/7.2].

Example 151 Production of(R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanol

To 2.5 ml of toluene, were added 701 mg (2.00 mmol) of(S)-[2-(3,4-dimethoxyphenyl)-1-methylethyl p-toluenesulfonate], 412 mg(2.40 mmol) of (R)-2-amino-1-(3-chlorophenyl)ethanol and 207 mg (1.50mmol) of anhydrous potassium carbonate, and the mixture was stirred at90° C. for 24 hours under nitrogen atmosphere. After adjusted toalkaline by adding a 10% aqueous solution of sodium hydroxide, thereaction mixture was extracted twice with 30 ml of toluene. The tolueneextract was dried over anhydrous sodium sulfate and subjected todistillation of the solvent and to purification with silica gelchromatography to afford 313 mg of 1-(3-chlorophenyl)-2- [[2-(3,4-dimethoxyphenyl) -1-methylethyl]amino]ethanol as white crystals(yield: 45%). As a result of isolating and analyzing the isomers withhigh performance liquid chromatography using an optical resolutioncolumn (column: Chiralpack AD (trade name), Daicel Chemical Industries,Ltd.), the optical purity of the title compound was 88.3%[(R,R)/(R,S)=88.3/11.7].

Example 152 Production of(R,R)-1-(3-chlorophenyl)-2-[[2-(3.4-dimethoxyphenyl)-1-methylethyl]amino]ethanol

The procedure of Example 151 was followed except for using 415 mg (3.00mmol) of anhydrous potassium carbonate to give 431 mg of1-(3-chlorophenyl)-2-[[2(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanol(yield: 62%). The optical purity of the title compound was 87.5%[(R,R)/(R,S)=87.5/12.5].

Examples 153 and 154 Production of(R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanol

The procedure of Example 151 was repeated except that the reaction wasconducted using the solvent at the reaction temperature shown in Table9. The results are set forth in Table 9.

TABLE 9 Reaction Optical temperature Yield purity Solvent (° C.) (%) (%)(R, R)/(R, S) Ex. 153 n-Octane 90 54 88.3 88.3/11.7 Ex. 154 Acetonitrile60 32 74.1 74.1/25.9

Examples 155 and 156 Production of(R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanol

The title compound was prepared in the same manner as in Example 151except that 5 ml of toluene was used and that the bases shown in Table10 were used instead of anhydrous potassium carbonate. The results areset forth in Table 10.

TABLE 10 Optical Yield Purity (R, R)/(R, S) Base (%) (%) (%) Ex. 155Sodium ethoxide 44 87.9 87.9/12.1 Ex. 156 Diisopropylamine 65 74.674.6/25.4

Example 157 Production of(R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanol

Under nitrogen atmosphere, 350 mg (1.00 mmol) of(S)-[2-(3,4-dimethoxyphenyl)-1-methylethyl p-toluenesulfonate] was addedto 206 mg (1.20 mmol) of (R)-2-amino-1-(3-chlorophenyl)ethanol, and themixture was stirred at 60° C. for 24 hours. The reaction mixture wasadded with a 10% aqueous solution of sodium hydroxide to be alkaline,and extracted twice with 30 ml of toluene. The toluene extract was driedover anhydrous sodium sulfate, and subjected to distillation of thesolvent and to purification with silica gel chromatography to give 187mg of1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanolas white crystals (yield: 54%). As a result of isolating and analyzingthe isomers by high performance liquid chromatography using an opticalresolution column (column: Chiralpack AD (trade name), Daicel ChemicalIndustries, Ltd.), the optical purity of the title compound was 95.2%[(R,R)/(R,S)=95.2/4.8].

Example 158 Production of(R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanol

To 274 mg (1.00 mmol) of (S)-[2-(3,4-dimethoxyphenyl)-1-methylethylmethanesulfonate] was added 206 mg (1.20 mmol) of(R)-2-amino-1-(3-chlorophenyl)ethanol, and the mixture was stirred at60° C. for 24 hours. The reaction mixture was added with a 10% aqueoussolution of sodium hydroxide to be alkaline, and extracted twice with 30ml of toluene. The toluene extract was dried over anhydrous sodiumsulfate, and subjected to distillation of the solvent and topurification with silica gel chromatography to give 161 mg of1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanolas white crystals (yield: 46%). As a result of isolating and analyzingthe isomers by high performance liquid chromatography using an opticalresolution column (column: Chiralpack AD (trade name), Daicel ChemicalIndustries, Ltd.), the optical purity of the title compound was 95.8%[(R,R)/(R,S)=95.8/4.2].

Example 159 Production of(R,R)-1-(3-chlorophenyl)-2-[[2-(3.4-dimethoxyphenyl)-1-methylethyl]amino]ethanol

The procedure of Example 158 was followed, except that 403 mg (2.35mmol) of (R)-2-amino-1-(3-chlorophenyl)ethanol was used, to give 252 mgof1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1methylethyl]amino]ethanol(yield: 72%). The optical purity of the title compound was 96.4%[(R,R)/(R,S)=96.4/3.6].

Example 160 Production of(R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanol

To 274 mg (1.00 mmol) of (S)-[2-(3,4-dimethoxyphenyl)-1-methylethylmethanesulfonate] were added 206 mg (1.20 mmol) of(R)-2-amino-1-(3-chlorophenyl)ethanol and 194 mg (1.50 mmol) ofdibutylamine, and the mixture was stirred at 60° C. for 24 hours undernitrogen atmosphere. The reaction mixture was added with a 10% aqueoussolution of sodium hydroxide to be alkaline, and extracted twice with 30ml of toluene. The toluene extract was dried over anhydrous sodiumsulfate, and subjected to distillation of the solvent and topurification with silica gel chromatography to give 190 mg of1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanolas white crystals (yield: 54%). As a result of isolating and analyzingthe isomers by high performance liquid chromatography using an opticalresolution column (column: Chiralpack AD (trade name), Daicel ChemicalIndustries, Ltd.), the optical purity of the objective compound was95.2% [(R,R)/(R,S)=95.2/4.8].

Examples 161 to 166 Production of(R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanol

The title compound was prepared in the same manner as in Example 160,except that the reaction was carried out using the base, instead ofdibutylamine, at the reaction temperature set forth in Table 11. Theresults are shown in Table 11.

TABLE 11 Reaction temper- Optical (R, R)/ ature Yield purity (R, S) Base(° C.) (%) (%) (%) Ex. 161 Dibutylamine 75 69 86.8  86.8/13.2 Ex. 162Triethylamine 60 47 96.9 96.9/3.1 Ex. 163 Pyridine 60 39 98.3 98.3/1.7Ex. 164 2-Pipecoline 60 57 96.0 96.0/4.0 Ex. 165 N-Methylmorpholine 6039 95.9 95.9/4.1 Ex. 166 N,N-Dimethyl- 60 44 95.3 95.3/4.7 ethanolamine

Example 167 Production of (S)-[2-(3,4dimethoxyohenyl)-1-methylethylmethanesulfonate

Under nitrogen atmosphere, to a methylene chloride solution (20 ml) of4.91 g (0.025 mol) of (S)-1-(3,4-dimethoxyphenyl)-2-propanol and 3.79 g(0.038 mol) of triethylamine, was added dropwise a methylene chloridesolution (10 ml) of 3.43 g (0.030 mol) of methanesulfonyl chloride undercooling with an ice bath for 30 minutes. The mixture was stirred for onehour, and the reaction was ceased by addition of 2N hydrochloric acid.The reaction mixture was extracted twice with 50 ml of methylenechloride. The methylene chloride extract was washed with a saturatedsolution of sodium chloride, dried and subjected to distillation of thesolvent to give 6.65 g of (S)-[2-(3,4-dimethoxyphenyl)-1-methylethylmethanesulfonate] as crystals (yield: 97%). As a result of the analysisby high performance liquid chromatography using an optical resolutioncolumn (column: Chiralpack AS (trade name), Daicel Chemical Industries,Ltd.), the optical purity of the title compound was 100%.

m.?.: 79.5 to 80.3° C.

[α]_(D) ²⁵ +26.5 (c=1.24, chloroform).

IR (KBr) (cm⁻¹) : 3018, 2973, 2937, 2843, 1607, 1590, 1518, 1469, 1447,1342, 1265, 1238, 1174, 1148, 1122, 1028, 984, 916, 883, 856, 828, 801,765, 719, 636, 546, 530, 477.

¹H-NMR (500 MHz, CDCl₃) δ: 6.82 (d, 1H), 6.77 (dd, 1H), 6.75 (d, 1H),4.89 (m, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 2.94 (dd, 1H), 2.85 (dd, 1H),2.60 (s, 3H), 1.45 (d, 3H).

What is claimed is:
 1. A process for producing an(S)-1-phenyl-2-substituted propane derivative which comprises: allowinga sulfonylating agent or a halogenating agent to react with an(S)-1-phenyl-2-propanol derivative shown by the following formula

wherein R¹ and R² represent (a) the same or different, a hydrogen atomor a protective group for hydroxyl group, or (b) R¹ and R² may form anoptionally substituted ring together with the adjacent oxygen atoms; andR³, R⁴ and R⁵ independently represent a hydrogen atom, a lower alkylgroup, a lower haloalkyl group, a lower alkoxy group, a nitro group or ahalogen atom, to produce an (S)-1-phenyl-2-substituted propanederivative shown by the following formula

wherein R¹, R², R³, R⁴ and R⁵ have the same meanings as defined above;and Y represents an optionally substituted alkylsulfonyloxy group, anoptionally substituted arylsulfonyloxy group or a halogen atom.
 2. Aprocess for producing an (S)-1-phenyl-2-substituted propane derivativeaccording to claim 1, which comprises: permitting a microorganism whichis capable of asymmetrically reducing a phenylacetone derivative shownby the following formula

wherein R¹ and R² represent (a) the same or different, a hydrogen atomor a protective group for hydroxyl group, or (b) R¹ and R² may form anoptionally substituted ring together with the adjacent oxygen atoms; andR³, R⁴ and R⁵ represent, independently, a hydrogen atom, a lower alkylgroup, a lower haloalkyl group, a lower alkoxy group, a nitro group or ahalogen atom, to produce the corresponding (S)-1-phenyl-2-propanolderivative shown by the formula (III), or a preparation thereof to acton said phenylacetone derivative of the formula (II), and allowing asulfonylating agent or a halogenating agent to react with the resultant(S)-1-phenyl-2-propanol derivative of the formula (III) to produce the(S)-1-1-phenyl-2-substituted propane derivative of the formula (IV).